Antitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T-cell–mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a coapplied therapy (oncolytic or suicide gene therapy) was promoted. This T-cell–mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFa and protein kinase C–dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both in vitro and in vivo. Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from first-line therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.
Bibliographical noteFunding Information:
The authors thank Toni L. Woltman for expert secretarial assistance. This work was funded in part by The European Research Council (to P.J. Selby), The Richard M. Schulze Family Foundation (to R.G. Vile), the Mayo Foundation (to R.G. Vile), Cancer Research UK (to K.J. Harrington and A. Melcher), the NIH (R01CA175386, R01CA108961 to R.G. Vile), The University of Minnesota and Mayo Clinic Partnership (to R.G. Vile) and a grant from Terry and Judith Paul (to J.S. Pulido), and a research grant from Oncolytics Biotech Inc (to R.G. Vile).
K.K. Smith is an employee at ArticulateScience LLC. R.S. Harris has ownership interest in ApoGen Biotechnologies and is a consultant/advisory board member for ApoGen Biotechnologies. M. Coffey is President and CEO at and has ownership interest in Oncolytics Biotech Inc. K.J. Harrington reports receiving commercial research funding from AstraZeneca, Bristol-Myers Squibb, Merck-Serono, and MSD; has received speakers bureau honoraria from AstraZeneca, Bristol-Myers Squibb, MerckSerono, and MSD; and is a consultant/advisory board member for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, MerckSerono, MSD, and Pfizer. No potential conflicts of interest were disclosed by the other authors.