1. Fuerst, Mark L.

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NEW YORK-Immunotherapeutic approaches could benefit subgroups of patients in different cancers, according to a study presented at the Second lnternational Cancer Immunotherapy Conference "Translating Science Into Survival."

tumor microenvironme... - Click to enlarge in new windowtumor microenvironments. tumor microenvironments

Tumors grow within a complex microenvironment composed of immune cells, fibroblasts, endothelial cells, and other non-malignant cells. "The study of the composition of tumor microenvironments has led to classifications with prognostic and theranostic values, as well as to treatments modulating composition and functional orientation. Concurrently, molecular classifications of tumors have proposed taxonomies that define groups of patients with different prognosis, which predict responses to treatments," said Wolf H. Fridman, MD, PhD, of the Cordeliers Research Centre in Paris, France.


The term "theranostics" was coined to define ongoing efforts in clinics to develop more specific, individualized therapies for various diseases, and to combine diagnostic and therapeutic capabilities into a single agent.


The density, location, and functional orientation of tumor-infiltrating lymphocytes within the immune system positively correlate in most cases with patient survival. He mentioned several examples.


"Colorectal cancer represents a paradigm for tumor immunology, as it is the human cancer in which it was exemplified that an adaptive immune response can control tumor growth and metastasis," said Fridman. "A high infiltration of Th1/cytotoxic T cells is associated with longer disease or progression free and/or overall survival both in primary and metastatic sites." He noted there are exceptions to this rule, such as renal cell carcinoma, where high CD8 T-cell infiltration correlates with shorter survival.


High infiltration by myeloid cells and fibroblasts is generally associated with poor prognosis in cancer. Fridman and colleagues have developed and validated a method, called MCP-counter, which simultaneously quantifies the proportions of 10 different cellular populations in human tissues. They have applied this method to human cancers.


"The method enabled a microenvironment-based classification of cancers that we correlated with known molecular classifications in colorectal and clear cell renal cell cancers. We confirmed our data by quantifying tumor infiltrating cells by immunohistochemistry," said Fridman.


In studying colorectal cancer, they found molecular and immune classifications confirmed that microsatellite-instable tumors as well as a subgroup of microsatellite-stable tumors are characterized by a favorable immune context with high Th1/cytotoxic infiltration. "Other subtypes exhibited poor immune infiltation or, in the worst prognostic case, high T-cell infiltration in the context of a major inflammatory, angiogenic, and desmoplastic reaction," he said.


A group of experts, including Fridman, met with the Fight Colorectal Cancer and the Cancer Research Institute recently to elaborate therapeutic strategies for the different subtypes of colorectal cancer. "In clear cell renal cell cancer, we identified a poor prognosis subgroup with high infiltration of CDB T cells which express checkpoint inhibitors in the presence of PDL-l and/or PDL-2 expressing tumor cells. In addition, using multiparametric immunophenotyping of tumor-infiltrating T cells, we characterized the lymphocyte populations that correlate with poor prognosis," said Fridman.


He concluded that "our analyses form the basis of a unification of molecular and immune classifications of human cancers, and challenge our current views of the relationship between the composition of the tumor microenvironment and patient's prognosis."


Immune Suppressive/Stimulating Monocytes

In another presentation at the meeting, Vincenzo Bronte, PhD, of the University of Verona in Italy, said the tumor environment is enriched in myeloid cells, which can either promote or fight tumor progression. "By releasing soluble mediators, such as cytokines, interleukins, metabolites, and growth factors, tumors stimulate a reactive myelopoiesis at both medullary and extra-medullary sites such as the spleen, which alters the steady-state myeloid differentiation, pushing proliferation and expansion of myeloid elements that acquire immunosuppressive and pro-tumoral functions," said Bronte.


This process is balanced between pro-survival and anti-apoptotic programs in myeloid cells. "The frequency and the function of myeloid-derived suppressor cells (MDSC) in the blood of tumor patients is now regarded as a negative prognostic marker, which correlates with the clinical outcome and response to therapy, including both conventional chemotherapy as well as immunotherapy," said Bronte. "Recent data suggest the monocytic compartment within MDSC (M-MDSC) in tumor-conditioned hosts is extremely plastic. Different pathways activated in M-MDSC, including the metabolism of the semi-essential amino acid L-arginine, exert a negative influence on the proliferation and functions of antigen-stimulated T lymphocytes."


The inability of T lymphocytes to recognize and destroy tumor cells can depend on the two enzymes involved in L-arginine metabolism. On the other hand, nitric oxide-producing cells derived from monocytes can support cancer cell destruction and tumor regression, he said.


"In fact, even though tumor-specific CD8+ T cells are negatively influenced by intratumoral L-arginine metabolism, they can license a set of monocytes to aid tumor rejection, which depends on increased tumor antigen presentation and nitric oxide synthase 2 induction, as the result of the intratumor activation of the CD40-CD40L axis," said Bronte.


Understanding the molecular events and cell biology of immune stimulating and immune suppressive monocytes "can provide additional targets to modify the tumor environment and enhance cancer immunotherapy," he concluded.


Mark L. Fuerst is a contributing writer.