Emerging roles for tumor stroma in antigen presentation and anti-cancer immunity

Author:

Papadas Athanasios12,Huang Yun12,Cicala Alexander12,Dou Yaling12,Fields Matteo123,Gibbons Alicia12,Hong Duncan12,Lagal Daniel J.12,Quintana Victoria12,Rizo Alejandro12,Zomalan Brolyn12,Asimakopoulos Fotis12ORCID

Affiliation:

1. 1Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A.

2. 2Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A.

3. 3Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy

Abstract

Advances in immunotherapy in the last decade have revolutionized treatment paradigms across multiple cancer diagnoses. However, only a minority of patients derive durable benefit and progress with traditional approaches, such as cancer vaccines, remains unsatisfactory. A key to overcoming these barriers resides with a deeper understanding of tumor antigen presentation and the complex and dynamic heterogeneity of tumor-infiltrating antigen-presenting cells (APCs). Reminiscent of the ‘second touch' hypothesis proposed by Klaus Ley for CD4+ T cell differentiation, the acquisition of full effector potential by lymph node- primed CD8+ T cells requires a second round of co-stimulation at the site where the antigen originated, i.e. the tumor bed. The tumor stroma holds a prime role in this process by hosting specialized APC niches, apparently distinct from tertiary lymphoid structures, that support second antigenic touch encounters and CD8+ T cell effector proliferation and differentiation. We propose that APC within second-touch niches become licensed for co-stimulation through stromal-derived instructive signals emulating embryonic or wound-healing provisional matrix remodeling. These immunostimulatory roles of stroma contrast with its widely accepted view as a physical and functional ‘immune barrier'. Stromal control of antigen presentation makes evolutionary sense as the host stroma-tumor interface constitutes the prime line of homeostatic ‘defense' against the emerging tumor. In this review, we outline how stroma-derived signals and cells regulate tumor antigen presentation and T-cell effector differentiation in the tumor bed. The re-definition of tumor stroma as immune rheostat rather than as inflexible immune barrier harbors significant untapped therapeutic opportunity.

Publisher

Portland Press Ltd.

Subject

Biochemistry

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