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

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.

Keywords: T-cells; antigen presentation; cancer; dendritic cells; stroma; vaccines.

Figure 1.. Specialized stromal APC niches support CD8+ T effector cell differentiation and anti-tumor immunity.

Following LN-priming, stem-like CD8+ T cells receive a ‘second touch' round of co-stimulation by APCs located within stromal niches along the tumor periphery. The resultant activation, proliferation and full effector differentiation of CD8+ T cells promotes ‘T-cell inflammation' of the tumor nest. We propose that APC within these niches receive instructive signals from peri-tumoral stroma, reminiscent of embryonic or adult wound-healing provisional matrix remodeling. Stromal signals license APC for co-stimulation and activation of CD8+ T cells. One such stromal signal is provided by versikine, a proteolytic fragment of the large-matrix proteoglycan versican (VCAN). In contrast with versikine, full-length VCAN promotes a tolerogenic APC phenotype, thus establishing a regulatory loop between the parent macromolecule (VCAN) and its derivative ‘matrikine'. Robust VCAN proteolysis is associated with T-cell inflammation across most solid and hematopoietic tumor types.

Figure 2.. Stromal versican proteolysis is associated with cDC1-CD8+ cross-talk and T-cell inflammation.

In human T-cell-inflamed tumors, CD8+ T-cells penetrate into tumor nests, whereas cDC1 interact with CD8+ T-cells within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an event associated with provisional matrix remodeling in embryonic development and adult wound healing [98]. Triple immunohistochemical staining of a human lung cancer biopsy [DPEAAE (versikine) = teal, XCR1 = brown, CD8 = purple]. XCR1 is a marker for cDC1. Magnification 400×.