Cancer immunotherapy has emerged as a treatment modality, mainly as the result of discoveries in the immune response regulation, including mechanisms that turn off immune responses. Immunogenic cutaneous melanoma is a canonical model for therapeutic immunotherapy studies. “Passive” immunotherapy with monoclonal antibodies (mAbs) has outpaced “active” immunotherapy with anti-tumor vaccines, and mAbs that antagonize the off responses have been recently introduced in clinical practice. Despite these recent successes, many unresolved practical and theoretical questions remain. Notably unknown are the identity of the lymphocytes that eliminate tumor cells, which white cells enter into tumors, through which endothelium, in what order, and how they perform their task. The parameters of size and location that could be used to determine in which tumors the immune response may be sufficient to eradicate the tumor are yet unknown. Immunotherapy has been so far more efficient to treat solid and hematologic tumors located outside the central nervous system, than primary brain tumors and brain metastases. In contrast to recent advances with mAbs, anti-tumor vaccine development has been lagging behind. The multiplicity of antigens that must be targeted to achieve significant clinical response is partially responsible for this lag, especially in melanoma, one of the most mutated tumors. Further hampering vaccination results is the fact that tumor elimination by the immune system is the result of a race between tumors with different growth rates and the relatively slow development of the adaptive immune response. The enhancement of the native arm of the immune response or the administration of targeted chemotherapy to slow tumor development, are approaches that should be studied. Finally, criteria used to analyze patient response to immunotherapeutic treatments must be perfected, and the patient populations that could benefit the most from this approach must be better defined.

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.

It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.