One microenvironment does not fit all: heterogeneity beyond cancer cells

Abstract

Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

“…Indeed, in our study, NK cell deficiency completely abolished the IL‐33‐mediated inhibition of tumor development in 4T1‐bearing mice, but not B16‐F10‐bearing mice. Besides, the heterogeneity of the TME also affects the antitumor immune response . Metastatic tumors are more sensitive to NK cells than CD8 + T cells, in contrast to primary tumors, in line with our observations in the 4T1 metastasis model.…”

“…Besides, the heterogeneity of the TME also affects the antitumor immune response. 45,46 Metastatic tumors are more sensitive to NK cells than CD8 + T cells, in contrast to primary tumors, 7 in line with our observations in the 4T1 metastasis model. Moreover, eosinophils are not always deleterious to tumor development, 47 even in the context of IL-33 overexpression in the tumor.…”

Basal‐subtype bladder tumours show a ‘hot’ immunophenotype

“…In addition, antibody evaluation and comparison by the use of TMAs has been previously performed in the evaluation of primary and metastatic bladder cancer samples with different PD‐L1 antibody clones, with good concordance, further supporting the use of TMAs . It is of note that heterogeneity of the immune microenvironment has also been discussed in the literature . These studies suggest co‐evolution of the immune microenvironment along with the tumour, and emphasise the inherent complexity of the immune microenvironment.…”

“…41 It is of note that heterogeneity of the immune microenvironment has also been discussed in the literature. [42][43][44] These studies suggest co-evolution of the immune microenvironment along with the tumour, and emphasise the inherent complexity of the immune microenvironment.…”

Tumor Heterogeneity: Will It Change What Pathologists Do

“…To begin with, by nature a tumor is composed of neoplastic cells set in a tissue infrastructure which we call the tumor stroma, the visual reflection of what in terms of tumor biology is known as the microenvironment. This is provided by the host, is part of the tumor tissue and an important co-determinant of tumor behavior but not composed of truly neoplastic cells [3][4][5]. The neoplastic cells proper, in most tumors do not look the same throughout the tumor.…”