harvard medical school cancer research

Cancer Immunology Program

The DF/HCC Cancer Immunology Program generates new insights into the mechanisms that regulate the anti-tumor immune response and translates this information into efficacious immunotherapies for cancer patients. The central hypothesis is that a deeper understanding of the requirements for effective innate and adaptive host responses will advance the development of treatment strategies that overcome tumor immune escape. Thematically, the Program is broadly divided into investigative efforts in strategies that enhance anti-tumor immune responses, including cancer vaccines, as well as bone marrow transplantation/adoptive cellular therapies.

The Program has supported the development and performance of multiple investigator-initiated clinical trials, which include immunoregulatory antibodies, adoptive therapy with tumor-specific CD8+ cytotoxic T cells, adoptive therapy with NKT cells, adoptive therapy with Epstein-Barr virus specific CD8+ T cells, dendritic cell-tumor cell fusion vaccines, genetically modified tumor cell vaccines, and combination therapies. Currently, the Program has more than 90 members.

Recent Publications

• Landoni E, Woodcock MG, Barragan G, Casirati G, Cinella V, Stucchi S, Flick LM, Withers TA, Hudson H, Casorati G, Dellabona P, Genovese P, Savoldo B, Metelitsa LS, Dotti G. IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity. Nat Commun 2024; 15:89. PubMed
• Cui A, Huang T, Li S, Ma A, Pérez JL, Sander C, Keskin DB, Wu CJ, Fraenkel E, Hacohen N. Dictionary of immune responses to cytokines at single-cell resolution. Nature 2024; 625:377-384. PubMed
• LaFleur MW, Lemmen AM, Streeter ISL, Nguyen TH, Milling LE, Derosia NM, Hoffman ZM, Gillis JE, Tjokrosurjo Q, Markson SC, Huang AY, Anekal PV, Montero Llopis P, Haining WN, Doench JG, Sharpe AH. X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system. Nat Immunol 2024; 25:178-188. PubMed
• Devant P, Dong Y, Mintseris J, Ma W, Gygi SP, Wu H, Kagan JC. Structural insights into cytokine cleavage by inflammatory caspase-4. Nature 2023. PubMed
• Yaghi OK, Hanna BS, Langston PK, Michelson DA, Jayewickreme T, Marin-Rodero M, Benoist C, Mathis D. A discrete 'early-responder' stromal-cell subtype orchestrates immunocyte recruitment to injured tissue. Nat Immunol 2023. PubMed
• Kim HJ, Nakagawa H, Choi JY, Che X, Divris A, Liu Q, Wight AE, Zhang H, Saad A, Solhjou Z, Deban C, Azzi JR, Cantor H. A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T-cells. J Clin Invest 2023. PubMed
• Schnell A, Huang L, Regan BML, Singh V, Vonficht D, Bollhagen A, Wang M, Hou Y, Bod L, Sobel RA, Chihara N, Madi A, Anderson AC, Regev A, Kuchroo VK. Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation. Nat Immunol 2023; 24:1908-1920. PubMed
• Baumgartner CK, Ebrahimi-Nik H, Iracheta-Vellve A, Hamel KM, Olander KE, Davis TGR, McGuire KA, Halvorsen GT, Avila OI, Patel CH, Kim SY, Kammula AV, Muscato AJ, Halliwill K, Geda P, Klinge KL, Xiong Z, Duggan R, Mu L, Yeary MD, Patti JC, Balon TM, Mathew R, Backus C, Kennedy DE, Chen A, Longenecker K, Klahn JT, Hrusch CL, Krishnan N, Hutchins CW, Dunning JP, Bulic M, Tiwari P, Colvin KJ, Chuong CL, Kohnle IC, Rees MG, Boghossian A, Ronan M, Roth JA, Wu MJ, Suermondt JSMT, Knudsen NH, Cheruiyot CK, Sen DR, Griffin GK, Golub TR, El-Bardeesy N, Decker JH, Yang Y, Guffroy M, Fossey S, Trusk P, Sun IM, Liu Y, Qiu W, Sun Q, Paddock MN, Farney EP, Matulenko MA, Beauregard C, Frost JM, Yates KB, Kym PR, Manguso RT. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature 2023; 622:850-862. PubMed
• Ali LR, Lenehan PJ, Cardot-Ruffino V, Dias Costa A, Katz MHG, Bauer TW, Nowak JA, Wolpin BM, Abrams TA, Patel A, Clancy TE, Wang J, Mancias JD, Reilley MJ, Stucky CH, Bekaii-Saab TS, Elias R, Merchant N, Slingluff CL, Rahma OE, Dougan SK. PD-1 blockade induces reactivation of non-productive T cell responses characterized by NF-kB signaling in patients with pancreatic cancer. Clin Cancer Res 2023. PubMed
• Wang Y, Drum DL, Sun R, Zhang Y, Chen F, Sun F, Dal E, Yu L, Jia J, Arya S, Jia L, Fan S, Isakoff SJ, Kehlmann AM, Dotti G, Liu F, Zheng H, Ferrone CR, Taghian AG, DeLeo AB, Ventin M, Cattaneo G, Li Y, Jounaidi Y, Huang P, Maccalli C, Zhang H, Wang C, Yang J, Boland GM, Sadreyev RI, Wong L, Ferrone S, Wang X. Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment. Nat Commun 2023; 14:5727. PubMed
• Oliveira G, Egloff AM, Afeyan AB, Wolff JO, Zeng Z, Chernock RD, Zhou L, Messier C, Lizotte P, Pfaff KL, Stromhaug K, Penter L, Haddad RI, Hanna GJ, Schoenfeld JD, Goguen LA, Annino DJ, Jo V, Oppelt P, Pipkorn P, Jackson R, Puram SV, Paniello RC, Rich JT, Webb J, Zevallos JP, Mansour M, Fu J, Dunn GP, Rodig SJ, Ley J, Morris LGT, Dunn L, Paweletz CP, Kallogjeri D, Piccirillo JF, Adkins DR, Wu CJ, Uppaluri R. Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer. Sci Immunol 2023; 8:eadf4968. PubMed
• Escobar G, Tooley K, Oliveras JP, Huang L, Cheng H, Bookstaver ML, Edwards C, Froimchuk E, Xue C, Mangani D, Krishnan RK, Hazel N, Rutigliani C, Jewell CM, Biasco L, Anderson AC. Tumor immunogenicity dictates reliance on TCF1 in CD8 T cells for response to immunotherapy. Cancer Cell 2023; 41:1662-1679.e7. PubMed
• Mota I, Patrucco E, Mastini C, Mahadevan NR, Thai TC, Bergaggio E, Cheong TC, Leonardi G, Karaca-Atabay E, Campisi M, Poggio T, Menotti M, Ambrogio C, Longo DL, Klaeger S, Keshishian H, Sztupinszki ZM, Szallasi Z, Keskin DB, Duke-Cohan JS, Reinhold B, Carr SA, Wu CJ, Moynihan KD, Irvine DJ, Barbie DA, Reinherz EL, Voena C, Awad MM, Blasco RB, Chiarle R. ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer. 2023. PubMed
• Li Y, Slavik KM, Toyoda HC, Morehouse BR, de Oliveira Mann CC, Elek A, Levy S, Wang Z, Mears KS, Liu J, Kashin D, Guo X, Mass T, Sebé-Pedrós A, Schwede F, Kranzusch PJ. cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell 2023. PubMed
• Al'Khafaji AM, Smith JT, Garimella KV, Babadi M, Popic V, Sade-Feldman M, Gatzen M, Sarkizova S, Schwartz MA, Blaum EM, Day A, Costello M, Bowers T, Gabriel S, Banks E, Philippakis AA, Boland GM, Blainey PC, Hacohen N. High-throughput RNA isoform sequencing using programmed cDNA concatenation. Nat Biotechnol 2023. PubMed
• Liu J, Bu X, Chu C, Dai X, Asara JM, Sicinski P, Freeman GJ, Wei W. PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity. Nat Commun 2023; 14:2806. PubMed
• Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, LaFleur MW, Johnson SB, Morad G, Park EM, Zhou Y, Watowich SS, Wargo JA, Freeman GJ, Kasper DL, Sharpe AH. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature 2023; 617:377-385. PubMed
• Lee JWJ, Plichta DR, Asher S, Delsignore M, Jeong T, McGoldrick J, Staller K, Khalili H, Xavier RJ, Chung DC. Association of distinct microbial signatures with premalignant colorectal adenomas. Cell Host Microbe 2023; 31:827-838.e3. PubMed
• Sen Santara S, Lee DJ, Crespo Â, Hu JJ, Walker C, Ma X, Zhang Y, Chowdhury S, Meza-Sosa KF, Lewandrowski M, Zhang H, Rowe M, McClelland A, Wu H, Junqueira C, Lieberman J. The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells. Nature 2023; 616:348-356. PubMed
• Hasegawa T, Oka T, Son HG, Oliver-García VS, Azin M, Eisenhaure TM, Lieb DJ, Hacohen N, Demehri S. Cytotoxic CD4 T cells eliminate senescent cells by targeting cytomegalovirus antigen. Cell 2023; 186:1417-1431.e20. PubMed
• Hanč P, Gonzalez RJ, Mazo IB, Wang Y, Lambert T, Ortiz G, Miller EW, von Andrian UH. Multimodal control of dendritic cell functions by nociceptors. Science 2023; 379:eabm5658. PubMed
• Walsh MJ, Stump CT, Kureshi R, Lenehan P, Ali LR, Dougan M, Knipe DM, Dougan SK. IFNγ is a central node of cancer immune equilibrium. Cell Rep 2023; 42:112219. PubMed
• Ito Y, Pan D, Zhang W, Zhang X, Juan TY, Pyrdol JW, Kyrysyuk O, Doench JG, Liu XS, Wucherpfennig KW. Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-secreted Cytokines. 2023. PubMed
• Gentili M, Liu B, Papanastasiou M, Dele-Oni D, Schwartz MA, Carlson RJ, Al'Khafaji AM, Krug K, Brown A, Doench JG, Carr SA, Hacohen N. ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling. Nat Commun 2023; 14:611. PubMed
• Sun Y, Revach OY, Anderson S, Kessler EA, Wolfe CH, Jenney A, Mills CE, Robitschek EJ, Davis TGR, Kim S, Fu A, Ma X, Gwee J, Tiwari P, Du PP, Sindurakar P, Tian J, Mehta A, Schneider AM, Yizhak K, Sade-Feldman M, LaSalle T, Sharova T, Xie H, Liu S, Michaud WA, Saad-Beretta R, Yates KB, Iracheta-Vellve A, Spetz JKE, Qin X, Sarosiek KA, Zhang G, Kim JW, Su MY, Cicerchia AM, Rasmussen MQ, Klempner SJ, Juric D, Pai SI, Miller DM, Giobbie-Hurder A, Chen JH, Pelka K, Frederick DT, Stinson S, Ivanova E, Aref AR, Paweletz CP, Barbie DA, Sen DR, Fisher DE, Corcoran RB, Hacohen N, Sorger PK, Flaherty KT, Boland GM, Manguso RT, Jenkins RW. Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 2023. PubMed
• Duke-Cohan JS, Akitsu A, Mallis RJ, Messier CM, Lizotte PH, Aster JC, Hwang W, Lang MJ, Reinherz EL. Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation. Nature 2022. PubMed
• Leavitt A, Yirmiya E, Amitai G, Lu A, Garb J, Herbst E, Morehouse BR, Hobbs SJ, Antine SP, Sun ZJ, Kranzusch PJ, Sorek R. Viruses inhibit TIR gcADPR signalling to overcome bacterial defence. Nature 2022; 611:326-331. PubMed
• Dubrot J, Du PP, Lane-Reticker SK, Kessler EA, Muscato AJ, Mehta A, Freeman SS, Allen PM, Olander KE, Ockerman KM, Wolfe CH, Wiesmann F, Knudsen NH, Tsao HW, Iracheta-Vellve A, Schneider EM, Rivera-Rosario AN, Kohnle IC, Pope HW, Ayer A, Mishra G, Zimmer MD, Kim SY, Mahapatra A, Ebrahimi-Nik H, Frederick DT, Boland GM, Haining WN, Root DE, Doench JG, Hacohen N, Yates KB, Manguso RT. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer. Nat Immunol 2022; 23:1495-1506. PubMed
• Haradhvala NJ, Leick MB, Maurer K, Gohil SH, Larson RC, Yao N, Gallagher KME, Katsis K, Frigault MJ, Southard J, Li S, Kann MC, Silva H, Jan M, Rhrissorrakrai K, Utro F, Levovitz C, Jacobs RA, Slowik K, Danysh BP, Livak KJ, Parida L, Ferry J, Jacobson C, Wu CJ, Getz G, Maus MV. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat Med 2022; 28:1848-1859. PubMed
• Bae M, Cassilly CD, Liu X, Park SM, Tusi BK, Chen X, Kwon J, Filipčík P, Bolze AS, Liu Z, Vlamakis H, Graham DB, Buhrlage SJ, Xavier RJ, Clardy J. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature 2022; 608:168-173. PubMed
• Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ. Cryo-EM structure of an active bacterial TIR-STING filament complex. Nature 2022. PubMed
• Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, Weiss S, Freeman GJ, Sharpe AH, Haigis MC. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8 T cells. Cell Metab 2022; 34:1137-1150.e6. PubMed
• Vining KH, Marneth AE, Adu-Berchie K, Grolman JM, Tringides CM, Liu Y, Wong WJ, Pozdnyakova O, Severgnini M, Stafford A, Duda GN, Hodi FS, Mullally A, Wucherpfennig KW, Mooney DJ. Mechanical checkpoint regulates monocyte differentiation in fibrotic niches. Nat Mater 2022; 21:939-950. PubMed
• Luoma AM, Suo S, Wang Y, Gunasti L, Porter CBM, Nabilsi N, Tadros J, Ferretti AP, Liao S, Gurer C, Chen YH, Criscitiello S, Ricker CA, Dionne D, Rozenblatt-Rosen O, Uppaluri R, Haddad RI, Ashenberg O, Regev A, Van Allen EM, MacBeath G, Schoenfeld JD, Wucherpfennig KW. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 2022; 185:2918-2935.e29. PubMed
• Yeo AT, Rawal S, Delcuze B, Christofides A, Atayde A, Strauss L, Balaj L, Rogers VA, Uhlmann EJ, Varma H, Carter BS, Boussiotis VA, Charest A. Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression. Nat Immunol 2022; 23:971-984. PubMed
• Badrinath S, Dellacherie MO, Li A, Zheng S, Zhang X, Sobral M, Pyrdol JW, Smith KL, Lu Y, Haag S, Ijaz H, Connor-Stroud F, Kaisho T, Dranoff G, Yuan GC, Mooney DJ, Wucherpfennig KW. A vaccine targeting resistant tumours by dual T cell plus NK cell attack. Nature 2022; 606:992-998. PubMed
• Hernández-Malmierca P, Vonficht D, Schnell A, Uckelmann HJ, Bollhagen A, Mahmoud MAA, Landua SL, van der Salm E, Trautmann CL, Raffel S, Grünschläger F, Lutz R, Ghosh M, Renders S, Correia N, Donato E, Dixon KO, Hirche C, Andresen C, Robens C, Werner PS, Boch T, Eisel D, Osen W, Pilz F, Przybylla A, Klein C, Buchholz F, Milsom MD, Essers MAG, Eichmüller SB, Hofmann WK, Nowak D, Hübschmann D, Hundemer M, Thiede C, Bullinger L, Müller-Tidow C, Armstrong SA, Trumpp A, Kuchroo VK, Haas S. Antigen presentation safeguards the integrity of the hematopoietic stem cell pool. Cell Stem Cell 2022; 29:760-775.e10. PubMed
• Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, Scarfó I, Leick MB, Grauwet K, Berger TR, Stewart K, Anekal PV, Jan M, Joung J, Schmidts A, Ouspenskaia T, Law T, Regev A, Getz G, Maus MV. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature 2022; 604:563-570. PubMed
• Leick MB, Silva H, Scarfò I, Larson R, Choi BD, Bouffard AA, Gallagher K, Schmidts A, Bailey SR, Kann MC, Jan M, Wehrli M, Grauwet K, Horick N, Frigault MJ, Maus MV. Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia. Cancer Cell 2022. PubMed
• Baldominos P, Barbera-Mourelle A, Barreiro O, Huang Y, Wight A, Cho JW, Zhao X, Estivill G, Adam I, Sanchez X, McCarthy S, Schaller J, Khan Z, Ruzo A, Pastorello R, Richardson ET, Dillon D, Montero-Llopis P, Barroso-Sousa R, Forman J, Shukla SA, Tolaney SM, Mittendorf EA, von Andrian UH, Wucherpfennig KW, Hemberg M, Agudo J. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell 2022. PubMed
• Ghosh S, Raundhal M, Myers SA, Carr SA, Chen X, Petsko GA, Glimcher LH. Identification of RIOK2 as a master regulator of human blood cell development. Nat Immunol 2022; 23:109-121. PubMed
• Johnson AG, Wein T, Mayer ML, Duncan-Lowey B, Yirmiya E, Oppenheimer-Shaanan Y, Amitai G, Sorek R, Kranzusch PJ. Bacterial gasdermins reveal an ancient mechanism of cell death. Science 2022; 375:221-225. PubMed
• Hobbs SJ, Wein T, Lu A, Morehouse BR, Schnabel J, Leavitt A, Yirmiya E, Sorek R, Kranzusch PJ. Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity. Nature 2022. PubMed
• Tang R, Acharya N, Subramanian A, Purohit V, Tabaka M, Hou Y, He D, Dixon KO, Lambden C, Xia J, Rozenblatt-Rosen O, Sobel RA, Wang C, Regev A, Anderson AC, Kuchroo VK. Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function. Sci Immunol 2022; 7:eabm0631. PubMed
• Meza-Sosa KF, Miao R, Navarro F, Zhang Z, Zhang Y, Hu JJ, Hartford CCR, Li XL, Pedraza-Alva G, Pérez-Martínez L, Lal A, Wu H, Lieberman J. SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage. Mol Cell 2022; 82:785-802.e10. PubMed
• Naranbhai V, St Denis KJ, Lam EC, Ofoman O, Garcia-Beltran WF, Mairena CB, Bhan AK, Gainor JF, Balazs AB, Iafrate AJ, . Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer. Cancer Cell 2022; 40:103-108.e2. PubMed
• Wang Y, Wang M, Djekidel MN, Chen H, Liu D, Alt FW, Zhang Y. eccDNAs are apoptotic products with high innate immunostimulatory activity. Nature 2021; 599:308-314. PubMed
• Naranbhai V, Pernat CA, Gavralidis A, St Denis KJ, Lam EC, Spring LM, Isakoff SJ, Farmer JR, Zubiri L, Hobbs GS, How J, Brunner AM, Fathi AT, Peterson JL, Sakhi M, Hambelton G, Denault EN, Mortensen LJ, Perriello LA, Bruno MN, Bertaux BY, Lawless AR, Jackson MA, Niehoff E, Barabell C, Nambu CN, Nakajima E, Reinicke T, Bowes C, Berrios-Mairena CJ, Ofoman O, Kirkpatrick GE, Thierauf JC, Reynolds K, Willers H, Beltran WG, Dighe AS, Saff R, Blumenthal K, Sullivan RJ, Chen YB, Kim A, Bardia A, Balazs AB, Iafrate AJ, Gainor JF. Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study. J Clin Oncol 2021. PubMed
• Pelka K, Hofree M, Chen JH, Sarkizova S, Pirl JD, Jorgji V, Bejnood A, Dionne D, Ge WH, Xu KH, Chao SX, Zollinger DR, Lieb DJ, Reeves JW, Fuhrman CA, Hoang ML, Delorey T, Nguyen LT, Waldman J, Klapholz M, Wakiro I, Cohen O, Albers J, Smillie CS, Cuoco MS, Wu J, Su MJ, Yeung J, Vijaykumar B, Magnuson AM, Asinovski N, Moll T, Goder-Reiser MN, Applebaum AS, Brais LK, DelloStritto LK, Denning SL, Phillips ST, Hill EK, Meehan JK, Frederick DT, Sharova T, Kanodia A, Todres EZ, Jané-Valbuena J, Biton M, Izar B, Lambden CD, Clancy TE, Bleday R, Melnitchouk N, Irani J, Kunitake H, Berger DL, Srivastava A, Hornick JL, Ogino S, Rotem A, Vigneau S, Johnson BE, Corcoran RB, Sharpe AH, Kuchroo VK, Ng K, Giannakis M, Nieman LT, Boland GM, Aguirre AJ, Anderson AC, Rozenblatt-Rosen O, Regev A, Hacohen N. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 2021; 184:4734-4752.e20. PubMed
• Jiang P, Zhang Y, Ru B, Yang Y, Vu T, Paul R, Mirza A, Altan-Bonnet G, Liu L, Ruppin E, Wakefield L, Wucherpfennig KW. Systematic investigation of cytokine signaling activity at the tissue and single-cell levels. Nat Methods 2021; 18:1181-1191. PubMed
• Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshinthala D, Verma A, Gaglia G, Nezu Y, Ke S, Qiu C, Ohuchida K, Oda Y, Lee TH, Wegiel B, Clohessy JG, London N, Santagata S, Wulf GM, Hidalgo M, Muthuswamy SK, Nakamura M, Gray NS, Zhou XZ, Lu KP. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell 2021. PubMed
• Slavik KM, Morehouse BR, Ragucci AE, Zhou W, Ai X, Chen Y, Li L, Wei Z, Bähre H, König M, Seifert R, Lee ASY, Cai H, Imler JL, Kranzusch PJ. cGAS-like receptors sense RNA and control 3'2'-cGAMP signalling in Drosophila. Nature 2021. PubMed
• Mysore V, Cullere X, Mears J, Rosetti F, Okubo K, Liew PX, Zhang F, Madera-Salcedo I, Rosenbauer F, Stone RM, Aster JC, von Andrian UH, Lichtman AH, Raychaudhuri S, Mayadas TN. FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity. Nat Commun 2021; 12:4791. PubMed
• Dixon KO, Tabaka M, Schramm MA, Xiao S, Tang R, Dionne D, Anderson AC, Rozenblatt-Rosen O, Regev A, Kuchroo VK. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 2021. PubMed
• Braun DA, Street K, Burke KP, Cookmeyer DL, Denize T, Pedersen CB, Gohil SH, Schindler N, Pomerance L, Hirsch L, Bakouny Z, Hou Y, Forman J, Huang T, Li S, Cui A, Keskin DB, Steinharter J, Bouchard G, Sun M, Pimenta EM, Xu W, Mahoney KM, McGregor BA, Hirsch MS, Chang SL, Livak KJ, McDermott DF, Shukla SA, Olsen LR, Signoretti S, Sharpe AH, Irizarry RA, Choueiri TK, Wu CJ. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 2021; 39:632-648.e8. PubMed
• Roehle K, Qiang L, Ventre KS, Heid D, Ali LR, Lenehan P, Heckler M, Crowley SJ, Stump CT, Ro G, Godicelj A, Bhuiyan AM, Yang A, Quiles Del Rey M, Biary T, Luoma AM, Bruck PT, Tegethoff JF, Nopper SL, Li J, Byrne KT, Pelletier M, Wucherpfennig KW, Stanger BZ, Akin JJ, Mancias JD, Agudo J, Dougan M, Dougan SK. cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes. Sci Transl Med 2021. PubMed
• Dai X, Bu X, Gao Y, Guo J, Hu J, Jiang C, Zhang Z, Xu K, Duan J, He S, Zhang J, Wan L, Liu T, Zhou X, Hung MC, Freeman GJ, Wei W. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol Cell 2021. PubMed
• Heckler M, Ali LR, Clancy-Thompson E, Qiang L, Ventre KS, Lenehan P, Roehle K, Luoma A, Boelaars K, Peters V, McCreary J, Boschert T, Wang ES, Suo S, Marangoni F, Mempel TR, Long HW, Wucherpfennig KW, Dougan M, Gray NS, Yuan GC, Goel S, Tolaney SM, Dougan SK. Inhibition of CDK4/6 promotes CD8 T-cell memory formation. 2021. PubMed
• Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, Wang L, Fu TM, Jacobson MP, Greka A, Lieberman J, Ruan J, Wu H. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 2021. PubMed
• Raundhal M, Ghosh S, Myers SA, Cuoco MS, Singer M, Carr SA, Waikar SS, Bonventre JV, Ritz J, Stone RM, Steensma DP, Regev A, Glimcher LH. Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias. Nat Immunol 2021; 22:520-529. PubMed
• Kumar S, Zeng Z, Bagati A, Tay RE, Sanz LA, Hartono SR, Ito Y, Abderazzaq F, Hatchi E, Jiang P, Cartwright ANR, Olawoyin O, Mathewson ND, Pyrdol JW, Li MZ, Doench JG, Booker MA, Tolstorukov MY, Elledge SJ, Chedin F, Liu XS, Wucherpfennig KW. CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells. 2021. PubMed
• Jerby-Arnon L, Neftel C, Shore ME, Weisman HR, Mathewson ND, McBride MJ, Haas B, Izar B, Volorio A, Boulay G, Cironi L, Richman AR, Broye LC, Gurski JM, Luo CC, Mylvaganam R, Nguyen L, Mei S, Melms JC, Georgescu C, Cohen O, Buendia-Buendia JE, Segerstolpe A, Sud M, Cuoco MS, Labes D, Gritsch S, Zollinger DR, Ortogero N, Beechem JM, Petur Nielsen G, Chebib I, Nguyen-Ngoc T, Montemurro M, Cote GM, Choy E, Letovanec I, Cherix S, Wagle N, Sorger PK, Haynes AB, Mullen JT, Stamenkovic I, Rivera MN, Kadoch C, Wucherpfennig KW, Rozenblatt-Rosen O, Suvà ML, Riggi N, Regev A. Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma. Nat Med 2021; 27:289-300. PubMed
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Arlene H. Sharpe, MD, PhD

Harvard Medical School

Kai W. Wucherpfennig, MD, PhD

Dana-Farber Cancer Institute

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How to realize immense promise of gene editing.

Nobel laureate Jennifer Doudna at Harvard Medical School.

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Alvin Powell

Harvard Staff Writer

Nobel-winning CRISPR pioneer says approval of revolutionary sickle-cell therapy shows need for more efficient, less expensive process 

The world stands on the edge of an era when gene editing can address many serious ills plaguing humankind, according to a pioneer of the revolutionary gene editing technique known as CRISPR-Cas9. But first, she said, there is a problem to solve.

Jennifer Doudna , whose work on CRISPR earned her the 2020 Nobel Prize in chemistry , applauded the recent approval of a CRISPR-based gene-editing therapy to help those struggling with sickle-cell disease. The therapy, developed by Boston-based Vertex Pharmaceuticals and CRISPR Therapeutics, was approved by the FDA in 2023. Preapproval studies showed it was very effective at reducing the severe pain that accompanies the life-threatening blood disorder.

Doudna, who visited Harvard Medical School last week to deliver the century-old Dunham Lectures, said the advance shows how CRISPR-based therapies can address hard-to-treat ailments, but it also highlights the hurdles that still stand in the way of widespread use. The therapy, she said, uses a process similar to that of a bone-marrow transplant. Blood stem cells are extracted from a patient’s bone marrow, genetically engineered, and then reinfused into the marrow to produce blood cells that greatly reduce disease symptoms and dangerous complications.

That process, while groundbreaking, is physically challenging for patients, and expensive, with each treatment costing more than $1 million. Together, those factors explain why only 250 people have received the therapy so far, Doudna said, even though the condition afflicts 90,000 to 100,000 in the U.S. and millions worldwide.

“It’s exciting, but that’s quite a small number,” Doudna said.

Doudna delivered her talk, “Rewriting the Future of Health Care with Genome Editing,” on Thursday in a packed Joseph B. Martin Amphitheater on HMS’ Longwood Campus in Boston.

She said that if CRISPR is to match its promise to reduce human suffering, new delivery methods are essential. She described several efforts underway in her lab and those of colleagues to create nanoparticle delivery systems that could, if perfected, relatively simply and cheaply deliver the CRISPR-based gene editor to target cells in various tissues.

That would allow the gene-editing process to occur inside the patient’s body rather than in the lab, as occurs with the new sickle-cell treatment. That would avoid the expensive and arduous process of extracting cells from a patient’s body, engineering them to address a condition’s genetic causes, and then reinjecting them into the patient.

“How we can achieve in vivo genome editing, I increasingly think this is the bottleneck in this field,” Doudna said. “Broadly speaking, what we need to be addressing is how these editors are going to get into target cells in the body. It’s a really interesting, really big challenge, and there’s many people working on it.”

The discovery of CRISPR/Cas9 in 2012 stemmed from basic scientific research into how bacteria fight off viruses. Researchers realized that a portion of the bacterial immune system contains molecules that precisely snip DNA at specific locations, and developed that into the molecular scissors of CRISPR/Cas9 that allow the precise editing of human, plant, and animal DNA at specific locations.

The technique was immediately seen as a major advance and other scientists began using it in their own research.

“Her groundbreaking development of CRISPR/Cas9 genome editing technology, with collaborator Emmanuelle Charpentier, earned the two of them the Nobel Prize in chemistry in 2020 and forever changed the course of human, animal, and agricultural research,” said Stephen Blacklow , chair of the HMS Department of Biological Chemistry and Molecular Pharmacology , who introduced Doudna. He added that Doudna has an “unsurpassed capacity to engage and inspire the next generation.”

Doudna, who received her Ph.D. from HMS’ Biological Chemistry and Molecular Pharmacology Department in 1989 under Nobel laureate Jack Szostak, expressed confidence that the problem of delivering gene-editing therapy directly to patients’ cells is a solvable one. Her talk dealt with strategies to tackle the problem including lentiviruses, lipid nanoparticles, and something called EDV — enveloped delivery vehicles.

“It makes me think that ultimately … we can come up with a strategy for a particle that will be both easy to make, easy to program, and be effective at delivering in vivo,” Doudna said.

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After 40 years of smoking, she survived lung cancer thanks to new treatments

Yuki Noguchi

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission. Denise Lee hide caption

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission.

Denise Lee grew up in Detroit in the mid-1970s and went to an all-girls Catholic high school. She smoked her first cigarette at age 14 at school, where cigarettes were a popular way of trying to lose weight.

Instead, her nicotine addiction lasted four decades until she quit in her mid-50s.

"At some point it got up as high as 2.5 packs a day," Lee, 62, recalls.

Yet she didn't think about lung cancer risk — until she saw a billboard urging former smokers to get screened. Lee, a retired lawyer living in Fremont, Calif., used to drive past it on her way to work.

"The thing that caught my attention was the fact that it was an African American female on the front," she recalls.

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The american cancer society says more people should get screened for lung cancer.

She eventually got the low-dose CT scan recommended for current and former smokers. When doctors found an early, but dangerous, tumor, Lee cried and panicked. Her mother had cared for her father, who'd died of prostate cancer. "My biggest concern was telling my mom," she says.

But that was six years ago, and Lee is cancer free today. Surgery removed the 2-inch tumor in her lung, then new treatments also boosted her immune system, fighting off any recurrence.

Lung cancer remains the most lethal form of the disease, killing about 135,000 Americans a year – more than breast, prostate and colon cancer combined – which is why many people still think of a diagnosis as synonymous with a death sentence. But with new treatments and technology, the survival rates from lung cancer are dramatically improving, allowing some patients with relatively late-stage cancers to live for years longer.

"If you're gonna have lung cancer, now is a good time," Lee says of the advances that saved her.

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective. Denise Lee hide caption

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective.

The key breakthrough, says Robert Winn, a lung cancer specialist at Virginia Commonwealth University, is the ability to better pinpoint the mutations of a patient's particular form of cancer. In the past, treatments were blunt tools that caused lots of collateral damage to healthy parts of the body while treating cancer.

"We've gone from that to molecular characterization of your lung cancer, and it has been a game changer," Winn says. "This is where science and innovation has an impact."

One of those game-changing treatments is called targeted therapy . Scientists identify genetic biomarkers in the mutated cancer cells to target and then deliver drugs that attack those targets, shrinking tumors.

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Another is immunotherapy, usually taken as a pill, which stimulates the body's own defense system to identify foreign cells, then uses the immune system's own power to fight the cancer as if it were a virus.

As scientists identify new cancer genes, they're creating an ever-broader array of these drugs.

Combined, these treatments have helped increase national survival rates by 22% in the past five years – a rapid improvement over a relatively short time, despite the fact that screening rates are very slow to increase. Winn says as these treatments get cheaper and readily available, the benefits are even reaching rural and Black populations with historic challenges accessing health care.

The most remarkable thing about the drugs is their ability to, in some cases, reverse late-stage cancers. Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital and faculty at Harvard Medical School, recalls seeing scans where large dark shadows of tumor would disappear: "It was remarkable to see the lung cancer completely melting away."

To Yang, such progress feels personal. He lost his beloved grandfather to the disease when Yang was in college. If he were diagnosed today, he might still be alive.

"Helping to take care of him was a big reason why I wanted to be a doctor," Yang says.

But the work of combating lung cancer is far from over; further progress in lung cancer survival hinges largely on getting more people screened.

Low-dose CT scans are recommended annually for those over 50 who smoked the equivalent of a pack a day for 20 years. But nationally, only 4.5% of those eligible get those scans , compared to rates of more than 75% for mammograms.

Andrea McKee, a radiation oncologist and spokesperson for the American Lung Association, says part of the problem is that lung cancer is associated with the stigma of smoking. Patients often blame themselves for the disease, saying: "'I know I did this to myself. And so I don't I don't think I deserve to get screened.'"

McKee says that's a challenge unique to lung cancer. "And it just boggles my mind when I hear that, because, of course, nobody deserves to die of lung cancer."

Denise Lee acknowledges that fear. "I was afraid of what they would find," she admits. But she urges friends and family to get yearly scans, anyway.

"I'm just so grateful that my diagnosis was early because then I had options," she says. "I could have surgery, I could have chemotherapy, I could be a part of a clinical trial."

And all of that saved her life.

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New study offers hope for a rare and devastating eye cancer

After more than a decade studying a rare eye cancer that produces some of the hardest-to-fight tumors, researchers from University of Pittsburgh Medical Center have found a treatment that works on some patients and, more importantly, a tool that can predict when it is likely to succeed.

The work, published in Nature Communications, is being validated in a clinical trial involving at least 30 patients. It could pave the way for similar methods designed to overcome one of the enduring frustrations of cancer care.

Because tumors differ, not only between patients but even inside the same patient, a treatment that works on one mass may fail on another, even when both are of the same cancer type.

The researchers in Pittsburgh tackled this problem in uveal melanoma, an eye cancer that afflicts only 5 people in a million, but that half the time spreads to other parts of the body, often the liver. The median survival once uveal melanoma has spread has been less than seven months, according to a 2018 study in the journal JAMA Ophthalmology.

“We chose this because it was one of the only cancers that 10 years ago when we started, there was nothing approved for it,” said Udai Kammula, who led the study and directs the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center in Pittsburgh.

Scientists had long speculated that the reason uveal melanoma is so tough to fight is that something helps the tumor keep out T cells, a key part of the body’s immune system that develops in bone marrow. However, previous studies by Kammula and his colleagues showed that uveal melanoma tumors actually have T cells inside, and they are turned on.

The problem? The cells lie dormant instead of multiplying and reaching numbers large enough to overwhelm the tumor.

The culprit appears to reside somewhere inside the tumor’s ecosystem of cells, molecules and blood vessels, known formally as the tumor’s “microenvironment.” Kammula compares this ecosystem to the infrastructure that supports a city. Something in that infrastructure helps protect uveal melanoma tumors by preventing the critical T cells from multiplying.

“Ultimately, if we’re going to get rid of cancer, we have to get rid of this infrastructure,” Kammula said.

A tool for predicting success

He and his colleagues have had some success using a treatment known as adoptive cell therapy, which was developed in the 1980s by Steven Rosenberg at the National Institutes of Health.

The treatment involves removing the T cells from the tumor, where they have been unable to proliferate. Scientists then take those T cells and grow them outside the body in a lab dish. They treat patients with chemotherapy to kill off the last of their old immune systems. Finally, they reinfuse the lab-grown T cells into the patient’s blood stream and the cells, now in much greater numbers, go on to attack the tumor.

In this treatment, the T cells are often referred to as tumor-infiltrating leukocytes, or TILs.

Kammula said his team has found that tumors shrink partially or completely in about 35 percent of patients who receive the treatment. But they wanted to know why it doesn’t work in the majority of cases, and whether there might be some way to predict beforehand when it will succeed.

To find out, the researchers analyzed samples from 100 different uveal melanoma tumors that had spread to different parts of the body in 84 patients, seeking to examine all of the tumors’ genetic material.

“We basically put the tumor biopsy in a blender that had the stroma [supportive tissue], the blood vessels, the immune cells, the tumor cells. It had everything,” Kammula said, explaining that they then analyzed all of the tumor’s genetic material.

They found 2,394 genes that could have helped make the tumor susceptible to treatment, some of them genes that experts would regard as “the usual suspects” and others that were unexpected. Using this long list of genes, the scientists searched for characteristics that they shared.

The genes were predominantly involved in helping the body defend itself against viruses, bacteria and other foreign invaders by removing the invaders and helping tissue heal. Kammula and the study’s lead author, Shravan Leonard-Murali, a postdoctoral fellow in the lab, used the different activity levels of these genes to develop a clinical tool.

The tool, known as a biomarker, assigns a score to a uveal melanoma tumor based on the likelihood that it will respond well to the treatment ― removing T cells, growing them outside the body, then reinfusing them.

So far, Kammula said, the biomarker has been “extremely good,” in predicting when the treatment will be effective, though he added, “these findings will need confirmation in the current ongoing clinical trial.”

“I thought it was somewhat of a tour de force, honestly,” said Eric Tran, an associate member of the Earle A. Chiles Research Institute, a division of Providence Cancer Institute in Portland, Ore. Tran did not participate in the study.

He said that while it will be important to validate these results, “I was certainly encouraged by their studies. And from my perspective, I wonder if that sort of strategy can be deployed in other cancers.”

Ryan J. Sullivan, an oncologist at Massachusetts General Hospital and associate professor at Harvard Medical School who was not involved in the study, called the team’s work “timely” and said “it is even more significant that they appear to have a [tool] that appears to predict which patients will benefit.”

The team at UPMC is already investigating possible wider application of both the treatment and the biomarker in a second clinical trial that involves a dozen different cancers.

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To See a Fossil Free Harvard, Reject Research Funding

This past week, I joined students across the Harvard community in celebrating “Intersectional Earth Week.” The event, hosted by Harvard Climate Coalition, featured teach-ins, affinity gatherings that centered on sustainable consumption, and other activities.

The success of Intersectional Earth Week reflects Harvard student support for environmentalist initiatives, but these aren’t the only strides Harvard has made towards a more sustainable campus in recent years.

In 2021, the Harvard Management Corporation declared it would divest from fossil fuels. A year later, the University announced the creation of the Salata Institute — an organization dedicated entirely to the clean energy transition and climate. And recently, the Faculty of Arts and Sciences significantly expanded the number of climate-oriented courses it offers.

Such initiatives indicate that Harvard is somewhat dedicated, or at least aware, of the importance of leading on the climate.

Despite this progress, none of Harvard’s schools possess an explicit policy for rejecting research funding from fossil fuel companies. One of the events of Intersectional Earth Week — a rally I organized with Fossil Fuel Divest Harvard — directly urged Harvard’s schools to disavow these funds. This is crucial because fossil fuel companies have historically funded disinformation campaigns for their economic benefit.

After scientists at Exxon routinely presented findings showing a link between carbon emissions and environmental destruction, the company decided to help create the “Global Climate Coalition.” This organization sowed doubt about research indicative of an impending climate crisis, impeding global climate agreements.

ExxonMobil has continued to meddle in climate research through the provision of research grants to universities — including Harvard.

Before fossil fuels, big tobacco also used research grants to manipulate studies in favor of their products.

In 1954, tobacco companies formed a research organization known as the “Tobacco Industry Research Company,” intending to dissuade the public that there was an explicit link between tobacco consumption and lung cancer. This misinformation undoubtedly resulted in significant health consequences given that smoking related illnesses are estimated to have led to the deaths of over 100 million people in the 20th century.

The Harvard T.H. Chan School of Public Health announced a policy in 2002 barring the acceptance of monetary assistance from the tobacco industry. Two years later, Harvard Medical School followed. Standing firm in their commitments to rejecting the tobacco industry’s research donations is a move that preserves the independence of their health research.

The lack of such a policy regarding fossil fuels similarly undermines our reputation as one of the world’s premier research institutions, and stalls Harvard’s ability to be a leader on climate.

Research studies that receive grants from fossil fuel companies tend to produce results that praise the benefits of non-renewable energy sources like oil and natural gas. However, research studies that do not tend to receive such funding paint a contrasting picture that more closely aligns with the scientific consensus on the detrimental effects of fossil fuel usage.

In order to ensure that researchers can remain objective in their scholarship, Harvard has an ethical imperative to reject grants from fossil fuel entities.

The climate crisis has significantly widespread health implications, similar to big tobacco. Take for example, higher rates of respiratory illness of communities located near major highways, or the myriad of deaths that have resulted from natural disasters in recent years. The evidence is clear — the climate crisis is actively damaging our health and livelihoods. By this logic, it is a moral imperative to create a similar funding policy for energy companies that rely on fossil fuels.

Despite no institutional policy, Harvard’s individual schools, departments, and researchers have a unique opportunity to lead the way on rejecting fossil fuel company grants.

While many researchers have already taken this pledge, my message to everyone, but especially students pursuing research at Harvard is clear: reject funding offers from fossil fuel companies.

Jasmine N. Wynn ’27, a Crimson Editorial editor, lives in Thayer Hall and is an organizer with Fossil Fuel Divest Harvard.

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Oral hygiene can reduce risk of some cancers

April 18, 2024—A healthy mouth microbiome can help prevent a number of diseases, including cancer , according to Harvard T.H. Chan School of Public Health’s Mingyang Song .

Song, associate professor of clinical epidemiology and nutrition, was among the experts quoted in an April 4 Everyday Health article about the connections between mouth, gum, and tooth health and overall health. “Alterations in the oral microbiome can cause systemic inflammation and increase disease risk indirectly,” Song explained. Microbes in the mouth can also travel to other parts of the body and directly increase the risk of conditions like diabetes , heart disease , Alzheimer’s disease , and various cancers, he added.

Previous studies co-authored by Song have shed light on the oral microbiome’s impacts on the risk of stomach and colorectal cancers. One study found that people with a history of gum disease have a 52% greater chance of developing stomach cancer compared with those without gum disease, and that losing two or more teeth raised stomach cancer risk by 33%. Another study found that people with gum disease had a 17% greater chance than those without gum disease of developing a serrated polyp—a type of polyp that can lead to colon cancer. The study also found that people who had lost at least four teeth had a 20% higher risk of a serrated polyp.

The takeaway, Song said, is to keep the mouth microbiome healthy. This can be accomplished through practicing oral hygiene—visiting the dentist regularly and brushing, flossing, and using mouthwash daily—as well as maintaining an overall healthy lifestyle through diet , exercise , and avoiding smoking .

Read the article in Everyday Health: The Health of Your Mouth May Affect Your Risk of Colorectal Cancer

– Maya Brownstein

Image: iStock/fizkes