Unleashing the power of NK cells in anticancer immunotherapy

Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.

Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy

Evidences highlight the role of various CD4+ helper T cells (CD4+ Th) subpopulations in orchestrating the immune responses against cancers. Epigenetics takes an important part in the regulation of CD4+ Th polarization and plasticity. In this review, we described the epigenetic factors that govern CD4+ T cells differentiation and recruitment in the tumor microenvironment and their subsequent involvement in the antitumor immunity. Finally, we discussed how to manipulate tumor reactive CD4+ Th responses by epigenetic drugs to improve anticancer immunotherapy.

Cancer environmental immunotherapy: starving tumor cell to death by targeting TGFB on immune cell

The blockage of intersectional communication between tumor and its metabolic and immune microenvironment is now considered a promising solution in treating cancer. Tumors have been identified as a special type of “wounds” that do not heal. Recent studies demonstrate that the lack of the transforming growth factor beta (TGFB) signaling pathway in CD4+ helper T cells induces the remodeling of the intratumoral vascular tissue, like healing “wounds” in damaged tissues caused by tumor overgrowth, which consequently prevents tumor cells from receiving the required nutrients in their microenvironment. TGFB blockade thereby promotes damaged tissue healing, causing tumor cell death as a result of starvation, ultimately obtaining an effective anticancer immunotherapy immune response. Here, we comment on the TGFB-mediated crosstalk between immune system and nutritional supply, highlighting cancer immunotherapeutic strategies targeting environmental immune-metabolism interplay. Cancer environmental immunotherapy targeting TGFB might therefore become one of the most promising treatment strategies for patients with cancer.

Spi-B Promotes the Recruitment of Tumor-Associated Macrophages via Enhancing CCL4 Expression in Lung Cancer

Tumor immune escape plays a critical role in malignant tumor progression and leads to the failure of anticancer immunotherapy. Spi-B, a lymphocyte lineage-specific Ets transcription factor, participates in mesenchymal invasion and favors metastasis in human lung cancer. However, the mechanism through which Spi-B regulates the tumor immune environment has not been elucidated. In this study, we demonstrated that Spi-B enhanced the infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment using subcutaneous mouse models and clinical samples of human lung cancer. Spi-B overexpression increased the expression of TAM polarization- and recruitment-related genes, including CCL4. Moreover, deleting CCL4 inhibited the ability of Spi-B promoting macrophage infiltration. These data suggest that Spi-B promotes the recruitment of TAMs to the tumor microenvironment via upregulating CCL4 expression, which contributes to the progression of lung cancer.

Dietary Impact in Association to Risk of Cancer and their Anticancer Immune Response

The imbalance between modulation of the cell proliferation and apoptosis results in abnormal cell production which ultimately leads to the cancerous condition. During the 21st century, cancer is probably exceeded to infectious and other chronic diseases as the major cause of death in all countries. The increasing global prevalence ratio and a speedily rising population of cancer survivors focus on the ferocity of public health and economic challenges pretended this disease. This review summarizes the significant outcomes of dietary intake which can enhance the immune response and reduce the risk of cancer. The nutritional general mechanism of action to influence the immune function and the potential activity of anticancer immunotherapy are also studied. For several cancers immunotherapy has developed into standard treatment but considerably remains to be done to prolong the activity of its potential efficiency mainly to cancers that are unaffected within each indication. Although a higher consumption of plant foods like vegetables, fruits, legumes, nuts and whole grains has been suggested for cancer prevention, it has been undecided what is the prime amount of ingestion of these foods and whether particular subtypes are valuable. Several million premature mortalities can be prevented if a high intake of plant foods is adopted globally. Furthermore, for reducing the risk of different types of cancers and slow down their development many dietary products have been proven advantageous. Keywords: Cancer, Immune system, Dietary items, Immunotherapy, Nutritional balance.

Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons

This review provides insight into the role of engineered T-cell receptors (TCRs) in immunotherapy. Novel approaches have been developed to boost anticancer immune system, including targeting new antigens, manufacturing new engineered or modified TCRs, and creating a safety switch for endo-suicide genes. In order to re-activate T cells against tumors, immune-mobilizing monoclonal TCRs against cancer (ImmTAC) have been developed as a novel class of manufactured molecules which are bispecific and recognize both cancer and T cells. The TCRs target special antigens such as NY-ESO-1, AHNAKS2580F or ERBB2H473Y to boost the efficacy of anticancer immunotherapy. The safety of genetically modified T cells is very important. Therefore, this review discusses pros and cons of different approaches, such as ImmTAC, Herpes simplex virus thymidine kinase (HSV-TK), and inducible caspase-9 in cancer immunotherapy. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. New approaches that can better detect antigens and drive an effective T cell response are discussed as well.

P14/ARF-Positive Malignant Pleural Mesothelioma: A Phenotype With Distinct Immune Microenvironment

IntroductionThe CDKN2A gene plays a central role in the pathogenesis of malignant pleural mesothelioma (MPM). The gene encodes for two tumor suppressor proteins, p16/INK4A and p14/ARF, frequently lost in MPM tumors. The exact role of p14/ARF in MPM and overall its correlation with the immune microenvironment is unknown. We aimed to determine whether there is a relationship between p14/ARF expression, tumor morphological features, and the inflammatory tumor microenvironment.MethodsDiagnostic biopsies from 76 chemo-naive MPMs were evaluated. Pathological assessments of histotype, necrosis, inflammation, grading, and mitosis were performed. We evaluated p14/ARF, PD-L1 (tumor proportion score, TPS), and Ki-67 (percentage) by immunohistochemistry. Inflammatory cell components (CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ and CD163+ macrophages) were quantified as percentages of positive cells, distinguishing between intratumoral and peritumoral areas. The expression of p14/ARF was associated with several clinical and pathological characteristics. A random forest-based machine-learning algorithm (Boruta) was implemented to identify which variables were associated with p14/ARF expression.Resultsp14/ARF was evaluated in 68 patients who had a sufficient number of tumor cells. Strong positivity was detected in 14 patients (21%) (11 epithelioid and 3 biphasic MPMs). At univariate analysis, p14/ARF-positive epithelioid mesotheliomas showed higher nuclear grade (G3) (p = 0.023) and higher PD-L1 expression (≥50%) (p = 0.042). The percentages of CD4 and CD163 in peritumoral areas were respectively higher and lower in p14/ARF positive tumors but did not reach statistical significance with our sample size (both p = 0.066). The Boruta algorithm confirmed the predictive value of PD-L1 percentage for p14/ARF expression in all histotypes.Conclusionsp14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression). Considering the results regarding the tumor immune microenvironment, p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors, being associated with low PD-L1 and CD4 expression, and high CD163 percentage. The association between p14/ARF-positive MPMs and PD-L1 expression suggests a possible interaction of the two pathways. Confirmation of our preliminary results could be important for patient selection and recruitment in future clinical trials with anticancer immunotherapy.

RNA Modification of N6-Methyladenosine Predicts Immune Phenotypes and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma

RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.