Peripheral CD4 T cell resistance to type I interferon defines outcome of PD1 blockade therapy in human cancer

Abstract

Abstract Type I interferons (IFN-Is) are paradoxically associated with both the success and failure of immune checkpoint blockade (ICB), with increased inflammation in the tumor associated with better response. To understand how IFN-Is modulate the immune response to ICB, we developed a mass cytometry approach to quantify pro- and anti-inflammatory features of IFN-I responsiveness at the single cell level. Using high dimensional analysis we show that the inflammatory responses that are beneficial in the peripheral blood are the opposite of what is considered beneficial in the tumor, thus identifying a functional disconnect between the peripheral and tumor immune compartments. We demonstrate that an initial resistance to IFN-I by CD4 T effector (Teff) cells in the peripheral blood is strongly associated to long-term benefit of anti-PD1 therapy in patients with melanoma, head and neck and lung cancers. By contrast, a strong IFN-I response correlates with progression and low survival probability. Upregulation of PDL1 by IFN-I did not relate to response, however patients with myeloid cells that initially reacted to IFN-I with higher IDO1 induction survived longer after anti-PD1. Single-cell RNA-sequencing stratified based on response to IFN-I identified transcriptional programs associated with therapy response, providing mechanistic insight into the peripheral cell states prior to therapy conducive to anti-PD1 success. Thus, contrary to a benefit of an initially inflamed tumor environment, an initially restrained CD4 Teff inflammatory response to IFN-I averts therapy failure and enables tumor control. This IFN-I response potential is a promising new biomarker for prediction of which patients will benefit most from anti-PD1 therapy. Supported by Canadian Institutes of Health Research (CIHR) Foundation Grant FDN148386, the Canadian Cancer Society (CCSRI) Innovation Award No. 706230, the National Institutes of Health (NIH) grant AI085043, The Terry Fox New Frontiers Grant the Scotiabank Research Chair to D.G.B, the Princess Margaret Hold’em for Life Cancer Research Fellowship (G. M. B).