Abstract
Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 767-775 |
| Number of pages | 9 |
| Journal | Nature medicine |
| Volume | 25 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Immunogenic neoantigens derived from gene fusions stimulate T cell responses. / Yang, Wei; Lee, Ken Wing; Srivastava, Raghvendra M.; Kuo, Fengshen; Krishna, Chirag; Chowell, Diego; Makarov, Vladimir; Hoen, Douglas; Dalin, Martin G.; Wexler, Leonard; Ghossein, Ronald; Katabi, Nora; Nadeem, Zaineb; Cohen, Marc A.; Tian, S. Ken; Robine, Nicolas; Arora, Kanika; Geiger, Heather; Agius, Phaedra; Bouvier, Nancy; Huberman, Kety; Vanness, Katelynd; Havel, Jonathan J.; Sims, Jennifer S.; Samstein, Robert M.; Mandal, Rajarsi; Tepe, Justin; Ganly, Ian; Ho, Alan L.; Riaz, Nadeem; Wong, Richard J.; Shukla, Neerav; Chan, Timothy A.; Morris, Luc G.T.
In: Nature medicine, Vol. 25, No. 5, 01.05.2019, p. 767-775.Research output: Contribution to journal › Letter
}
TY - JOUR
T1 - Immunogenic neoantigens derived from gene fusions stimulate T cell responses
AU - Yang, Wei
AU - Lee, Ken Wing
AU - Srivastava, Raghvendra M.
AU - Kuo, Fengshen
AU - Krishna, Chirag
AU - Chowell, Diego
AU - Makarov, Vladimir
AU - Hoen, Douglas
AU - Dalin, Martin G.
AU - Wexler, Leonard
AU - Ghossein, Ronald
AU - Katabi, Nora
AU - Nadeem, Zaineb
AU - Cohen, Marc A.
AU - Tian, S. Ken
AU - Robine, Nicolas
AU - Arora, Kanika
AU - Geiger, Heather
AU - Agius, Phaedra
AU - Bouvier, Nancy
AU - Huberman, Kety
AU - Vanness, Katelynd
AU - Havel, Jonathan J.
AU - Sims, Jennifer S.
AU - Samstein, Robert M.
AU - Mandal, Rajarsi
AU - Tepe, Justin
AU - Ganly, Ian
AU - Ho, Alan L.
AU - Riaz, Nadeem
AU - Wong, Richard J.
AU - Shukla, Neerav
AU - Chan, Timothy A.
AU - Morris, Luc G.T.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.
AB - Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.
UR - http://www.scopus.com/inward/record.url?scp=85064683074&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064683074&partnerID=8YFLogxK
U2 - 10.1038/s41591-019-0434-2
DO - 10.1038/s41591-019-0434-2
M3 - Letter
C2 - 31011208
AN - SCOPUS:85064683074
VL - 25
SP - 767
EP - 775
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -