The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

Neoadjuvant immunotherapy involves administering immune checkpoint inhibitors (ICIs) before surgical resection in high-risk resectable disease. This strategy was shown to have a high pathological response rate and prolonged relapse-free survival in randomized trials in melanoma, glioblastoma, and colon cancer with small numbers of patients. In resectable cancers, ICIs such as anti-programmed cell death-1 (PD1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) can enhance anti-tumor immunity by activating antigen-specific T-cells found in the primary tumor. These tumor-reactive T-cells continue to exert anti-tumor effects on remaining neoplastic cells after the resection of the primary tumor, potentially preventing relapses from occurring. Based on the scientific rationale and early clinical observations with surrogate survival endpoints, neoadjuvant immunotherapy may provide an effective alternative to other therapeutic strategies such as adjuvant treatment. However, this can only be determined by conducting randomized controlled trials comparing neoadjuvant immunotherapy to the current standard of care for each tumor site. This review will discuss the cellular mechanisms that occur during successful neoadjuvant immunotherapy and highlight the clinical data from the available human studies that support the preclinical mechanistic data. Here we also discuss strategies required for successful neoadjuvant immunotherapy, including combination treatment strategies and resistance mechanisms to neoadjuvant treatment.

Members of the transient receptor potential (TRP) family of ion channels are cellular sensors involved in numerous physiological and pathological processes. We identified the TRP subfamily M member 7 (TRPM7) channel-kinase as a previously uncharacterized regulator of B cell activation. We showed that TRPM7 played a critical role in the early events of B cell activation through both its ion channel and kinase functions. DT40 B cells deficient in TRPM7 or expressing a kinase-deficient mutant of TRPM7 showed defective gathering of antigen and prolonged B cell receptor (BCR) signaling. We showed that lipid metabolism was altered in TRPM7-deficient cells and in cells expressing a kinase-deficient mutant of TRPM7 and suggest that PLC-γ2 may be a target of the kinase activity of TRPM7. Primary B cells that expressed less TRPM7 or were treated with a pharmacological inhibitor of TRPM7 also displayed defective antigen gathering and increased BCR signaling. Finally, we demonstrated that blocking TRPM7 function compromised antigen internalization and presentation to T cells. These data suggest that TRPM7 controls an essential process required for B cell affinity maturation and the production of high-affinity antibodies.

The transient receptor potential (TRP) family is a large family of widely expressed ion channels that regulate the intracellular concentration of ions and metals and respond to various chemical and physical stimuli. TRP subfamily M member 7 (TRPM7) is unusual in that it contains both an ion channel and a kinase domain. TRPM7 is a divalent cation channel with preference for Ca and Mg It is required for the survival of DT40 cells, a B cell line; however, deletion of TRPM7 in T cells does not impair their development. We found that expression of TRPM7 was required for B cell development in mice. Mice that lacked TRPM7 in B cells failed to generate peripheral B cells because of a developmental block at the pro-B cell stage. The loss of TRPM7 kinase activity alone did not affect the proportion of peripheral mature B cells or the development of B cells in the bone marrow. However, supplementation with a high concentration of extracellular Mg partially rescued the development of TRPM7-deficient B cells in vitro. Thus, our findings identify a critical role for TRPM7 ion channel activity in B cell development.

Pancreatic cancer has a high mortality rate, and its incidence is increasing worldwide. The almost universal poor prognosis of pancreatic cancer is partly due to symptoms presenting only at late stages and limited effective treatments. Recently, immune checkpoint blockade inhibitors have drastically improved patient survival in metastatic and advanced settings in certain cancers. Unfortunately, these therapies are ineffective in pancreatic cancer. However, tumor biopsies from long-term survivors of pancreatic cancer are more likely to be infiltrated by cytotoxic T-cells and certain species of bacteria that activate T-cells. These observations suggest that T-cell activation is essential for anti-tumor immunity in pancreatic cancers. This review discusses the immunological mechanisms responsible for effective anti-tumor immunity and how immune-based strategies can be exploited to develop new pancreatic cancer treatments.

Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) capable of recognizing stressed and infected cells through multiple germ line-encoded receptor-ligand interactions. Missing-self recognition involves NK cell sensing of the loss of host-encoded inhibitory ligands on target cells, including MHC class I (MHC-I) molecules and other MHC-I-independent ligands. Mouse cytomegalovirus (MCMV) infection promotes a rapid host-mediated loss of the inhibitory NKR-P1B ligand Clr-b (encoded by Clec2d) on infected cells. Here we provide evidence that an MCMV m145 family member, m153, functions to stabilize cell surface Clr-b during MCMV infection. Ectopic expression of m153 in fibroblasts augments Clr-b cell surface levels. Moreover, infections using m153-deficient MCMV mutants (Δm144-m158 and Δm153) show an accelerated and exacerbated Clr-b downregulation. Importantly, enhanced loss of Clr-b during Δm153 mutant infection reverts to wild-type levels upon exogenous m153 complementation in fibroblasts. While the effects of m153 on Clr-b levels are independent of Clec2d transcription, imaging experiments revealed that the m153 and Clr-b proteins only minimally colocalize within the same subcellular compartments, and tagged versions of the proteins were refractory to coimmunoprecipitation under mild-detergent conditions. Surprisingly, the Δm153 mutant possesses enhanced virulence in vivo, independent of both Clr-b and NKR-P1B, suggesting that m153 potentially targets additional host factors. Nevertheless, the present data highlight a unique mechanism by which MCMV modulates NK ligand expression. IMPORTANCE Cytomegaloviruses are betaherpesviruses that in immunocompromised individuals can lead to severe pathologies. These viruses encode various gene products that serve to evade innate immune recognition. NK cells are among the first immune cells that respond to CMV infection and use germ line-encoded NK cell receptors (NKR) to distinguish healthy from virus-infected cells. One such axis that plays a critical role in NK recognition involves the inhibitory NKR-P1B receptor, which engages the host ligand Clr-b, a molecule commonly lost on stressed cells (“missing-self”). In this study, we discovered that mouse CMV utilizes the m153 glycoprotein to circumvent host-mediated Clr-b downregulation, in order to evade NK recognition. These results highlight a novel MCMV-mediated immune evasion strategy.

BackgroundCheckpoint inhibitors have changed the outcomes for patients with advanced melanoma. However, many patients still show primary resistance to single-agent therapy. Recently, the role of the gut microbiome in influencing antitumor immunity has been established. Currently, various methods of modifying the gut microbiome of cancer patients are being explored. We report the initial safety results of the first two patients treated on a phase I study combining Fecal Microbiota Transplantation (FMT) with single-agent anti-PD1 in treatment-naïve patients with advanced melanoma.MethodsTwo healthy donors were selected through our screening process and approximately 100 grams of fresh stool was processed and prepared for FMT as per our standardized protocol. FMT recipients were melanoma patients with unresectable or metastatic disease who were treatment naïve for their advanced disease. Bowel preparation was completed the day prior and FMT was performed using oral administration of approximately 40 capsules. Anti-PD1 was started at least 1 week after FMT to allow for microbiome engraftment. Blood and stool were analyzed at baseline (pre-FMT), before immunotherapy, and three weeks after it.ResultsPatient 1 was diagnosed with recurrent melanoma of the lower limb with multiple in-transit lesions refractory to control with surgery and a single intralesional injection of IL-2. Patient received stool from Donor 1 and did not experience any adverse effects from FMT. At the time of treatment #4, a solitary large cutaneous lesion stabilized but the patient experienced grade 1 diarrhoea, grade 2 nausea, and grade 2 fatigue, and grade 2 depression (NCI-CTCAE v5.0). Patient 2 was diagnosed with recurrent melanoma of the parotid gland with metastatic lesions in the lungs. Patient 2 received stool from Donor 2 and experienced only grade 1 flatus from FMT. At the time of treatment #3, the patient experienced grade 1 constipation. Both patients had a vigorous immune response to FMT measured by changes in the immune subpopulations in peripheral blood one week after FMT, including an increase in CD28+ CD8+ T cells and a decrease in PDL1+ CD3- cells. Following anti-PD1 therapy, both patients had an increase in CD39+ CD8+ T cell population. The PD1+ CD38+ CD8+ dysfunctional T cell levels decreased in both patients post-FMT and anti-PD1 therapy.ConclusionsFMT combined with anti-PD1 therapy in patients with advanced melanoma appears to be safe. A measurable immune response was observed one week after FMT in both patients. One patient experienced several grade 2 toxicities with stabilization of a large cutaneous lesion.AcknowledgementsThis study is funded by a grant from The Lotte & John Hecht Memorial Foundation and a grant from The Medical Oncology Research Funds (MORF) from Western University.Trial RegistrationNCT03772899Ethics ApprovalThe study was approved by Western University Institutution‘s Ethics Board, approval number 113131, date of approval March 15, 2019.

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