Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy

Abstract

Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions.

Analysis of the Single-Cell Heterogeneity of Adenocarcinoma Cell Lines and the Investigation of Intratumor Heterogeneity Reveals the Expression of Transmembrane Protein 45A (TMEM45A) in Lung Adenocarcinoma Cancer Patients

“…A recent whole-genome sequencing study of 2658 tumor samples representing 38 cancer types underlined the selection of subclonal driver mutations behind ITH [ 47 ]. ITH may fundamentally originate from the variable genomic, transcriptomic, epigenetic, and proteomic states of single cells within a bulk tumor mass [ 48 , 49 ]. Wu et al recently investigated 42 NSCLC patients by single-cell RNA sequencing and revealed their ITH by transcriptome analysis [ 50 ].…”

Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies

“…Due to high variability of single subclone-or multiple subclone-induced tumor evolution in the same tumor or metastatic regions of the same tumor, as well as in different types of GI cancers, intratumoral genomic heterogeneity is highly beneficial for early diagnosis via liquid biopsy (345)(346)(347), while intertumoral heterogeneity-mediated changes of temporal and spatial plasticity and stemness in the TME precisely support the significance of comprehensive therapeutic principle (348,349). Complexity of tumor heterogeneity essentially reflects adaption of genomic heterogeneity to selective pressure and utility of angiogenesis and immunosuppression through the TME for distant metastasis (350)(351)(352). Tumor heterogeneity also strongly indicates that rebuilding immune normalization to block interaction of intertumoral heterogeneity with the TME is a practical methodology to alter cancer therapy to chronic disease management.…”

The role of immunogenic cell death in gastrointestinal cancer immunotherapy (Review)

“…Interestingly, combination treatment of cellular adoptive transfer and chemotherapy can improve clinical outcomes and may prevent recurrence in patients with advance GC that may be attributed to the synergistic effect of ICD ( 115 ). Moreover, multiclonal elimination of tumor cells could be improved by using multi-peptide vaccine or broad-array tumor antigen ( 116 , 117 ). Overall, these would be the solution for immune exhaustion in clinical settings of adoptive therapies.…”

“…improved by using multi-peptide vaccine or broad-array tumor antigen (116,117). Overall, these would be the solution for immune exhaustion in clinical settings of adoptive therapies.…”