Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy

Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy.

Pan-Cancer Analysis of Immune Cell Infiltration Identifies a Prognostic Immune-Cell Characteristic Score (ICCS) in Lung Adenocarcinoma

“…Subsequently, we used the ssGSEA to characterize and quantify the tumor-infiltrating immune cells from their gene expression data across multiple cancers. Among the 32 types of cancer, 9,112 individual tumor samples can be divided into two clusters: High CI and Low CI phenotypes, which can be interpreted as “hot” and “cold” tumors ( 34 ). High CI was associated with better prognosis in ACC, CESC, CHOL, HNSC, LIHC, LUAD, SARC, and SKCM and worse prognosis in GBM, LGG, and UVM, indicating a heterogeneous prognostic outcome depending on the cancer type.…”

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

“…Abnormalities within the TME are strongly associated with repressed anticancer immunity, which profoundly impacts the effectiveness of immunotherapy ( 11 , 17 – 19 ). Thus, therapeutic reprogramming of specific immune components of the TME with combination treatments, such as immunosuppressive cell types, may overcome TME-induced resistance to checkpoint blockade, thereby enhancing or reinvigorating anticancer immunity ( 17 , 20 ). ICIs in combination with treatment modalities such as chemotherapy, targeted agents and CTLA-4 antibodies have been successfully developed and further studies are ongoing to evaluate other combination approaches including radiation and immune modulators [recently reviewed by Murciano-Goroff et al.…”

Case Report: Significant Response to the Combination of Lenvatinib and Immune Checkpoint Inhibitor in a Patient With Heavily Pretreated Metastatic Triple Negative Breast Cancer

“…Recent studies have emphasized the critical role of the tumor microenvironment (TME) ( 21 ). The presence of CD8+ tumor-infiltrating lymphocytes that are reactive to clonal neoantigens are associated with durable clinical benefit of the treatment with ICIs ( 22 ).…”