E-102 Destruction of the tumor microenvironment by neoantigen-specific T cells prevents relapse of therapy-resistant cancer variants
Authors: Wolf Steven , Schreiber Karin , Steiner Madeline , Weichselbaum Ralph , Leisegang Matthias , Schreiber Hans 
Published: April 2019

Microorganisms frequently escape host defenses by generating heritable variants. Cancer cells replicate more slowly than most microorganisms, but variants nevertheless arise frequently because malignant cells carry numerous mutations and are genetically very instable. Thus, chemo-, radiation and/or immunotherapy may stabilize or even reduce a solid tumor, but relapse is common due to outgrowth of therapy-resistant variants. We discovered that destruction of the cancer microenvironment by T cells recognizing neoantigens, which arise from cancer mutations1, eliminates such variants, thereby preventing relapse.2 The cancer microenvironment, also referred to as stroma (Greek, bed), contains mostly macrophages and fibroblasts,3 in addition to tumor capillaries. While tumor macrophages are bone marrow (BM)-derived, tumor-associated fibroblasts as well as tumor endothelial cells are derived from sessile precursors.2 When tumor stroma is destroyed by neoantigen-specific T cells, cancer cells are deprived of essential attachment or paracrine growth factors that are essential for all cancer cells including their variants to grow and survive.4,5 At least in some tumor models, both the BM-derived as well as non-BM-derived cells must be targeted by the T cells. Also, both cell types must express the receptors for IFNγ and TNF and T cells must be able to produce both cytokines.6 IFNγ alone is inefficient to destroy tumor vessels.7 However, when stromal microenvironment is destroyed, the ensuing cancer cell destruction is not selective for cancer cells expressing the antigen or the antigen-presenting MHC Class I molecule; thus escape variants are equally well eradicated.

We discovered that destruction of the cancer microenvironment by neoantigen-specific T cells can be achieved by multiple different approaches. When neoantigen expression on the cancer cells is high, and can be cross-presented by stromal cells, then tumor stroma is sensitized and killed directly by T cells. Cancer variants embedded in the stroma are also destroyed and relapse is prevented.2 When neoantigen expression level on the cancer cells is low, local irradiation of the tumor can temporarily up-regulated the level of cross-presented antigen on stromal cells to allow stromal destruction by T cells and relapse is being prevented.8 When cancer cells lack the MHC Class I but maintains neoantigen expression, neoantigen released from the cancer cells can still be cross-presented by stromal cells. CD8+ T cells destroy these stromal cells and thereby much of the tumor mass, even though residual cancer cells persist for months without escape by antigen loss variants.9 Finally, the CD8+ T cells after having maintained the equilibrium for months become exhausted which results in tumor escape.10 Escape is also common when autochthonous mutant antigens are targeted by CD8+ T cells. These cancer-specific antigens are caused by non-synonymous single nucleotide variants (nsSNVs)1 and are often expressed at low levels.11 In these situations, recognition of additional antigens on the cancer cells by CD4+ T cells may be needed.11 Even though most cancer cells are MHC Class II negative, they release the antigen into the tumor stroma where it is cross-presented by MHC Class II positive stromal macrophages. Using antigen models, we could show that CD4+ T cells indeed cooperate with CD8+ T cells and this interaction occurs at the effector phase.12 Such CD4+ T cells could rescue CD8+ T cells in anti-PD-L1 resistant tumors and lead to cancer eradication.11

1. Monach PMID:7600302

2. Spiotto PMID:14981514

3. Arina PMC4941507

4. Singh PMID:1309851

5. Seung PMC:41496

6. Zhang PMC226202

7. Kammertoens PMID:28445461

8. Zhang PMC2118433

9. Zhang PMID:18316622

10. Arina PMC5354300

11. Leisegang PMID: 26667491

12. Schietinger PMC2964573