Managing the TME to improve the efficacy of cancer therapy

Abstract

The tumor microenvironment (TME) influences tumor growth, metastatic spread and response to treatment. Often immunosuppression, mediated by the TME, impairs a beneficial response. The complexity of the tumor composition challenges our abilities to design new and more effective therapies. Going forward we will need to 'manage' the content and or functionality of the TME to improve treatment outcomes. Currently, several different kinds of treatments are available to patients with cancer: there are the traditional approaches of chemotherapy, radiation and surgery; there are targeted agents that inhibit kinases associated with oncogenic pathways; there are monoclonal antibodies that target surface antigens often delivering toxic payloads or cells and finally there are antibodies and biologics that seek to overcome the immunosuppression caused by elements within the TME. How each of these therapies interact with the TME is currently under intense and widespread investigation. In this review we describe how the TME and its immunosuppressive components can influence both tumor progression and response to treatment focusing on three particular tumor types, classic Hodgkin Lymphoma (cHL), Pancreatic Ductal Adenocarcinoma (PDAC) and Glioblastoma Multiforme (GBM). And, finally, we offer five approaches to manipulate or manage the TME to improve outcomes for cancer patients.

Keywords: GBM - glioblastoma multiforme; Hodgkin (cHL); PDAC - pancreatic ductal adenocarcinoma; TME (tumor microenvironment); anti-cancer therapy; immunosuppression; immunotherapy combined therapy.

Figure 1

Schematic representation of immunosuppressive cells in the TME. In this scheme the major immune cells involved in the anti-tumor or pro-tumor response are highlighted. TANs and TAMs secrete TGF-β, Il-10 and ARG-I, which inhibit the cytotoxic activity of NK cells and T cells. Moreover, TAMs promote the conversion of normal fibroblasts into CAFs, which in turn promote the proliferation of tumor cells. In this immunosuppressive microenvironment DCs, through the secretion of IL-10 and overexpression of IDO, prevent the activation of T cells, avoiding the recognition of the tumoral antigens expressed on MHC. Another immunosuppressive population is represented by MDSCs that inhibit the activation of T cells, and furthermore allow the activation of Tregs, in particular increasing the expression of CTLA4 on the surface of Treg themselves. Moreover, Tregs inhibit the cytotoxic functionality of the CTLs, where PD-1 and Fas are increased to inhibit the anti-tumoral response. Finally, the endothelium contributes to immunosuppression, since these cells express FasL.

Figure 2

TME and its composition in three different cancer model. (A) PDAC TME is characterized by a dense stroma, CAFs, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). Pancreatic cancer cells typically express one or more mutated oncogenes or tumor suppressor genes (e.g. KRAS, TP53, CDKN2A, and SMAD4) that can interact with the TME, regulating stromal cells and the ECM in direct and indirect ways. The TME has highly diverse cellular and extracellular components. The CAFs are responsible for the secretion of extracellular matrix and soluble molecules which create a TME that favors tumor growth and resistance to the therapy. The TME is highly immunosuppressive, with the infiltration of TAMs, MDSC and Treg. The accumulation of CD4+ T cells and B cells contribute to carcinogenesis too. The soluble molecules released by PDAC cells or immune cells recreate an immunosuppressive microenvironment. IL-6, IL-1, TNF-α favor the polarization of macrophages into TAMs and they promote MDSC function, through the secretion of ECM. TGF-β is released by cancer cells and by immunosuppressive cells to favor a pro-tumoral environment. Here are represented some chemokines responsible for the recruitment of immune cells into the tumor, and involved in the redirection of the T cells, for example CCL5 attracts Tregs, CXCL12-CXCR4 restricts lymphocyte migration and keeps CTLs outside the tumor. (B) The TME surrounding malignant GBM is very complex. Indeed, the interaction between the immune system and the brain interior is problematic because of the presence of the blood-brain barrier. Even though, also in GBM the TME plays an important role. The GBM cells are heterogeneic they present antigen to CD4 and CD8 T cells that usually are dysfunctional and exhausted. Few B cells infiltrate in the brain. Moreover, GBM is characterized by an immunosuppressive and inflammatory microenvironment composed of cytokines (IL6, IL1-β, TGF-β, IL-10 and prostaglandin E2), chemokines, and regulatory immune-suppressive cells (Treg, TAMs, and MDSCs). Leukocyte recruitment to the tumor site is mediated by inflammatory chemokines from the CXC subfamily and CC group which attract leukocytes within tumor and exert pro- or anti-tumoral effects. CXCL8 is one of the inflammatory chemokines and the axis CXCL8-CXCR1/2 axis belongs to the most important and the best recognized regulatory factors in the development of CNS tumors. Moreover, CXCL8, CCL2, IL-6, contribute to MDSC generation (45). (C) cHL is characterized by a peculiar TME, most of the tumor is represented by dysfunctional T lymphocytes and by immunosuppressive cellular and acellular components. IL-10 and TGF-β, produced by RS, allow the accumulation of Tregs involved in the suppression of the activity of effector cells. IL-10 is a potent immune suppressive cytokine. Levels of IL-10 are elevated in up to a half of cHL patients and are correlated to disease aggressiveness and poor response to therapy. TGF-β production contributes to depress T-cell proliferation, cytokine release, and cytolytic activity. The soluble factor, prostaglandin E2 (PGE2), interferes with T cell receptor signaling, and decreases the cytotoxic response. IL-4, IL-13 and M-CSF attract myeloid cells and polarize macrophages into MDSC and TAMs (46).

Figure 3

Targeting the TME as possible therapeutic approach.(1) Promote T cell migration into cold tumors by targeting CXCR4-CXCL12 interaction. (2) Reduce tumor-associated myeloid cells by using JAK/STAT inhibitors. (3) Target Tregs with antibodies to CD25 or similar surface antigen. (4) Increase T cell activation by adding Het-IL15. (5) Increase tumor-associated mutations by administrating inhibitors of DNA repair, TMZ or radiation to allow neoantigens to drive a robust immune response.