Coordination of Intratumoral Immune Reaction and Human Colorectal Cancer Recurrence

Abstract

A role for the immune system in controlling the progression of solid tumors has been established in several mouse models. However, the effect of immune responses and tumor escape on patient prognosis in the context of human cancer is poorly understood. Here, we investigate the cellular and molecular parameters that could describe in situ immune responses in human colorectal cancer according to clinical parameters of metastatic lymph node or distant organ invasion (METAÀ or META+ patients). Primary tumor samples of colorectal carcinoma were analyzed by integrating large-scale phenotypic ( flow cytometry, 39 patients) and gene expression (real time reverse transcription-PCR, 103 patients) data sets related to immune and protumoral processes. In METAÀ colorectal cancer primary tumors with high densities of T cells, we observed significant positive correlations between markers of innate immune cells [tumor-associated macrophages, dendritic cells, natural killer (NK) cells, and NKT cells] and markers of early-activated T cells. Significant correlations were also observed between markers of cytotoxic and effector memory T-cell subpopulations. These correlation profiles were absent in tumors with low T-cell infiltrates and were altered in META+ tumors with high T-cell infiltrates. We show that the coexpression of genes mediating cytotoxicity (GNLY) and Th1 adaptive immune responses (IRF1) accurately predicted patient survival independently of the metastatic status. High intratumoral mRNA expression of the proangiogenic mediator vascular endothelial growth factor was associated with significantly reduced survival rates in patients expressing high mRNA levels of GNLY. Investigation of the colorectal cancer primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response.

Immune infiltration in human tumors: a prognostic factor that should not be ignored

“…In addition, we found by immunohistochemistry on a large cohort of 435 patients that high numbers of CD8 þ T cells among T cells correlated with lack of metastasis and protection against tumor recurrence (Camus et al, 2009). Finally, analysis of gene expression in 103 patients revealed that, although associated with no prognostic effect by itself, high VEGF gene …”

“…However, our current observations in CRC and lung cancer suggest that this might also occur in the tumor. Strikingly, a strong correlation was found with the presence of innate cells, including DC and the group of CRC patients with high density of T cells and no detectable metastases, whereas the immune response was disorganized in patients with low T-cell numbers and detectable metastases (Camus et al, 2009). Similarly, in early stage NSCLC, the density of mature DCs, which home exclusively in the T-cell areas of tertiary lymphoid structures, was highly associated with a favorable clinical outcome .…”

“…were almost absent from primary tumors of metastatic patients with high lymphocyte infiltration whereas there were no significant differences in early and late memory T cells (Camus et al, 2009; Figure 1). In addition, we found by immunohistochemistry on a large cohort of 435 patients that high numbers of CD8 þ T cells among T cells correlated with lack of metastasis and protection against tumor recurrence (Camus et al, 2009).…”

Immunogenic death of colon cancer cells treated with oxaliplatin

“…Oxaliplatin is mostly used for the treatment of CRC (Muggia and Fojo, 2004;Kelland, 2007), a tumor type prognosis of which is profoundly influenced by the type, density and location of lymphoid infiltrates in tumor beds (Pages et al, 2005;Galon et al, 2006). Thus, even in advanced CRC, the presence of markers of cytotoxic T cells and T helper 1-adaptative responses has a positive prognostic impact (Galon et al, 2006;Camus et al, 2009).…”

Colon cancer cells produce immunoregulatory glucocorticoids

“…Many cancer cells aberrantly overexpress cellular proteins or neo-antigens, which can be recognized by the immune system and provoke anti-tumor immune responses (van den Broek et al, 1996;Smyth et al, 2000;Shankaran et al, 2001). Also, CRC cells are often immunogenic and can stimulate the activation of tumor-specific lymphocytes (Camus et al, 2009). Therefore, anti-tumor immune responses may significantly contribute to tumor immune surveillance and limit tumor development and growth.…”