Burger et al. expressed pairs of neoantigens in KP mouse lung adenocarcinomas to demonstrate that during tumor development, concurrently expressed neoantigens compete and establish an antigen dominance hierarchy, resulting in suppressed T cell expansion, differentiation, and effector function against the subdominant antigen. Subdominant T cell responses were enriched for a dysfunctional subset of CCR6+TCF1+ progenitor cells with Tc17 differentiation trajectory, and associated with poor response to ICB in both humans and mice. Therapeutic vaccination eliminated CCR6+TCF1+ cells and improved the subdominant response.
Contributed by Shishir Pant
ABSTRACT: CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (2) David H. Koch Institute for Integrative Cancer Res
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (2) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. (4) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (5) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (6) Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA. (7) Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA. (8) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. (9) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02215, USA. (10) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.
