Background Many cancer immunotherapies depend on the ability of cytotoxic CD8+ T cells to recognize neoantigens on MHCI complexes to effectively eliminate tumor cells. However, patient response following immunotherapy is highly variable, with recent work suggesting that neoantigen expression patterns can impair patient response. Specifically, it was observed that the immune response is dampened when neoantigens are expressed only by a subset of tumor cells (heterogeneous expression).1 To study why anti-tumor immunity is reduced in a heterogeneous setting we developed a transplant murine tumor model engineered to express neoantigens in a heterogeneous pattern or homogenously.
Methods A curated list of neoantigens with varying predicted MCHI binding affinities was used to established an array of cell lines expressing at one to three neoantigens. The lines were inoculated subcutaneously in immunocompetent mice as mixtures (heterogenous) or as a single line (homogenous) to study the resulting immune response. Tumors were harvested at days 7, 10 and 14 and flow cytometry analysis was used to phenotype infiltrating immune populations, including antigen-specific CD8+ T cells. ELISpot assays were performed using splenocytes from the same timepoints to determine the frequency of antigen-specific T cells in the periphery.
Results Compared to neoantigens predicted to bind weakly to MHCI, neoantigens predicted to bind strongly elicited robust expansion of antigen-specific T cells in the periphery and tumors expressing these antigens alone exhibited greater numbers of tumor infiltrating T cells. Homogenous expression of two neoantigens was found to enhance anti-tumor immunity by increasing the frequency of tumor-reactive T cells. Further, homogenous expression of two neoantigens induced protective immunity against antigens, including those that failed to be controlled when expressed alone.
Conclusions Using our novel reductionist tumor model, our results suggest that a more robust response against weak antigens could be induced if a response against a strong, highly immunogenic neoantigen is mounted simultaneously. This observation has direct implications for the design of neoantigen vaccines either as mono- or combination immunotherapies, especially in the setting of a heterogeneous neoantigen expression pattern.
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016 Mar 25;351(6280):1463–9.
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