Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

Mirjana Efremova,Dietmar Rieder,Zlatko Trajanoski,Gottfried Baier,Anne Krogsdam,Martin Löwer,Hubert Hackl,Francesca Finotello,Victoria Klepsch,Natascha Hermann-Kleiter,Pornpimol Charoentong

doi:10.1038/s41467-017-02424-0

Abstract

The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates immunoediting. The immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure.

Highlights

The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome
The MC38 murine colorectal cancer (CRC) cell line is derived from a grade-III adenocarcinoma that was chemically induced in a female C57BL/6 mouse and used since as a transplantable mouse tumor model[14]
With the development of immunotherapies with checkpoint blockers as well as other immunotherapeutic strategies, including therapeutic vaccines and engineered T cells[40], the interaction of the tumor and the immune system, and the question of how the cancer genome is edited came into focus

Summary

Introduction

The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. The definitive work supporting the existence of this process was published 30 years later by the Schreiber lab[2] In this seminal work, an elegant experiment was carried out using a mouse model lacking the recombination activating gene 2 (RAG2), which encodes a protein involved in the initiation of V(D)J recombination during Band T-cell development. The cancer immunoediting postulates a dual role of the immunity in the complex interactions between tumor and host; the immune system, by recognizing tumor-specific antigens, protects the host through elimination of tumor cells, but can sculpt the developing tumor by editing the cancer genome, thereby producing variants with reduced immunogenicity. As neither longitudinal samples of wild-type or immunodeficient mice nor checkpoint blockade was applied, two major questions remain unanswered: (1) To what extent is T-cell-dependent immunoselection sculpting the cancer genome? We perform experiments with anti-PD-L1 antibodies using the MC38 cell line and another CRC cell line which is a model for non-hypermutated/MSI- CRC (CT26 (Colon Tumor #26)) and show how targeting the PD-1/ PD-L1 pathway modulates immunoediting

Methods

Results

Conclusion