Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2018 Jul 1

PMID 29958801

Citations 388

Authors

Jinyang Li

Katelyn T Byrne

Fangxue Yan

Taiji Yamazoe

Zeyu Chen

Timour Baslan

Lee P Richman

Jeffrey H Lin

Yu H Sun

Andrew J Rech

David Balli

Ceire A Hay

Yogev Sela

Allyson J Merrell

Shannon M Liudahl

Naomi Gordon

Robert J Norgard

Salina Yuan

Sixiang Yu

Timothy Chao

Shuai Ye

T S Karin Eisinger-Mathason

Robert B Faryabi

John W Tobias

Scott W Lowe

Lisa M Coussens

E John Wherry

Robert H Vonderheide

Ben Z Stanger

Affiliations

Soon will be listed here.

Abstract

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8 T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

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