Checkpoint blockade‐based immunotherapy in the context of tumor microenvironment: Opportunities and challenges

Abstract

A dynamic and mutualistic interaction between tumor cells and tumor microenvironment (TME) promotes the progression and metastasis of solid tumors. Cancer immunotherapy is becoming a major treatment paradigm for a variety of cancers. Although immunotherapy, especially the use of immune checkpoint inhibitors, has achieved clinical success, only a minority of patients exhibits durable responses. Clinical studies directed at identifying appropriate biomarkers and immune profiles that can be used to predict immunotherapy responses are presently being conducted. Combining treatment strategies tailored to cancer‐immune interactions are designed to increase the rate of durable clinical response in patients. It is essential to establish a reasonable tumor classification strategy according to TME to improve cancer immunotherapy. In the current review, a modified classification of TME is proposed, and optimization of TME classification is needed through detailed and integrated molecular characterization of large patient cohorts in the future.

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

“…Moreover, increased exhausted CD8+ T cells results in a reduced anti-leukemia response in patients [28]. Interestingly, Tim-3 + CD4+ and Tim-3 + CD244 + CD4+ T cells primarily accumulated in the BM group, which may suggest that the AML BM microenvironment also has effects on CD4+ T cells, leading to higher expression of Tim-3 with the exhausted phenotype, as it is known that upregulating Tim-3 reduces the activation of T cells [34,35]. It is interesting that the phenotype of exhausted T cell is distinct in different T cell subsets between BM and PB.…”

Mechanisms of Action of Drugs Effective in Hepatocellular Carcinoma

“…When PD‐1 binds its ligand, it inhibits a set of kinases, which triggers the blockage of CD28 and TCR signaling, thereby inhibiting T cell immune response. The blockage of this pathway enhances antitumor immune responses by means of amplification of the T cell response, avoidance of T cell exhaustion, and reduction of regulatory T cell function . IC inhibitors are monoclonal antibodies able to disrupt ligand‐receptor interaction (Fig.…”

“…). This provided the rationale to develop IC inhibitors and reinvigorate the immune antitumor response as new anticancer therapies . So far, two IC inhibitors (i.e., nivolumab and pembrolizumab) have shown efficacy in single‐arm phase 2 trials in HCC as measured by a response rate of approximately 20%.…”

“…This could reveal synergistic effects or act on mechanisms of primary or acquired resistance. For example, the combinations of lenvatinib/pembrolizumab or regorafenib/pembrolizumab have shown promising results with unprecedented response rates greater than 40% . Unlike other solid tumors, HCC lacks any predictive biomarker of response to any of the drugs shown to be effective in phase 3 trials.…”

Resistance to immune checkpoint inhibitors. Next steps and combinational approaches

“…Potential combination strategies of an immune checkpoint inhibitors (CPI) in order to overcome resistance based on the immune phenotype. MDSC myeloid-derived suppressor cells (Modified and adapted,[14,25])…”