Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues

Abstract

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Targeting MS4A4A: A novel pathway to improve immunotherapy responses in glioblastoma

“…Prior studies have indicated that M2 macrophages are commonly linked to immune suppression, and the polarization state of these macrophages may influence the efficacy of immune suppressive signals. Therefore, we hypothesize that C4 cell clusters constitute the pivotal cell clusters in glioma patients who resist PD‐1 therapy 51,52 …”

“…Therefore, we hypothesize that C4 cell clusters constitute the pivotal cell clusters in glioma patients who resist PD-1 therapy. 51,52 We conducted differential analysis on the gene expression profiles in the C4 cell cluster between the Non and Res groups. We identified 147 upregulated genes and 3 downregulated genes.…”

Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers

“…14,[34][35][36] We observed several immune-oncology-related signatures that favored aoBTC versus eoBTC, namely, IFG, TIS, and differences in angiogenesis enrichment. [37][38][39][40] Despite the differences, the distribution of inflamed tumors was not significantly different in the two groups. Moreover, in assessing the TME with respect to immune cell infiltration, no significant differences could be identified.…”

Prognostic value of lymphocyte-to-monocyte ratio in gastric cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

“…TAMs directly affect regulatory T-cells, impeding tumor immunity while accelerating angiogenesis and the degeneration of the extracellular matrix. These actions promote the development and progression of tumors ( 43 , 44 ). As a result, TAMs can be considered an indicator of a high cancer burden.…”