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The presence of a tumor can alter host immunity systematically. The immune-tumor interaction in one site may impact the local immune microenvironment in distal tissues through the circulation, and therefore influence the efficacy of immunotherapies to distant metastases. Improved understanding of the immune-tumor interactions during immunotherapy treatment in a metastatic setting may enhance the efficacy of current immunotherapies. Here we investigate the response to αPD-1/αCTLA4 and trimAb (αDR5, α4-1BB, αCD40) of 67NR murine breast tumors grown simultaneously in the mammary fat pad (MFP) and lung, a common site of breast cancer metastasis, and compared to tumors grown in isolation. Lung tumors present in isolation were resistant to both therapies. However, in MFP and lung tumor-bearing mice, the presence of a MFP tumor could increase lung tumor response to immunotherapy and decrease the number of lung metastases, leading to complete eradication of lung tumors in a proportion of mice. The MFP tumor influence on lung metastases was mediated by CD8+ T cells, as CD8+ T cell depletion abolished the difference in lung metastases. Furthermore, mice with concomitant MFP and lung tumors had increased tumor specific, effector CD8+ T cells infiltration in the lungs. Thus, we propose a model where tumors in an immunogenic location can give rise to systemic anti-tumor CD8+ T cell responses that could be utilized to target metastatic tumors. These results highlight the requirement for clinical consideration of cross-talk between primary and metastatic tumors for effective immunotherapy for cancers otherwise resistant to immunotherapy.

Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours.

In our recent study, we show that tumoral CD73 expression limits the efficacy of anti-PD-1 therapy, and this is rescued by concomitant A2A blockade. Since CD73 is known to be overexpressed in several human cancers and A2A antagonists have undergone clinical trials for Parkinson's Disease, this combination warrants further investigation.

Advanced stages of cancer often involve multiple tumors in different locations in the body. These tumors are associated with a microenvironment that can influence tumor responses to immunotherapy. Whether tumors and their disparate microenvironment can interact together at distance in a multiple tumor setting, through a form of cross-talk, and affect their responses to immunotherapy has never been described. Our study investigated the cross-talk between two tumors with disparate microenvironments in a mouse model. We demonstrated that immunosuppressive visceral tumors could influence distant subcutaneous (SC) tumors to render them resistant to immunotherapy. We observed distinct modifications in the SC tumor microenvironment following cross-talk with kidney tumors that exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumor was present in the mouse, the SC tumors were highly infiltrated with M2 macrophages and had a reduced T cell and NK cell effector immune profile. Finally, blocking the M2-associated chemokine CCL2 or depleting macrophages, significantly improved the effect of immunotherapy on growth of SC tumors in the presence of concomitant kidney tumors. This work emphasizes the potential negative influence that a tumor, with a strong immunosuppressive microenvironment, can exert on distant tumors that would normally be treatment-responsive. This report may lead to a new vision of the prioritization in the treatment of advanced metastatic cancer.

The specific targeting of tumor-elicited immunosuppression is a promising strategy for the treatment of cancer. We have recently demonstrated that targeting the immunosuppressive pathway mediated by CD73-derived adenosine through the blockade of A2A/A2B adenosine receptors significantly reduced the metastatic potential of CD73+ breast carcinomas and melanomas via both immunological and non-immunological mechanisms.

The presence of an immunosuppressive microenvironment can limit the full potential of adoptive T cell immunotherapy. However, specific blockade of the PD-1 immunosuppressive pathway can significantly enhance the function of gene-modified T cells expressing a chimeric antigen receptor (CAR) leading to enhanced tumor eradication.

The tumor microenvironment is a complex assortment of cells that includes a variety of leukocytes. The overall effect of the microenvironment is to support the growth of tumors and suppress immune responses. Immunotherapy is a highly promising form of cancer treatment, but its efficacy can be severely compromised by an immunosuppressive tumor microenvironment. Chemotherapy and radiation treatment can mediate tumor reduction through cytotoxic effects, but it is becoming increasingly clear that these forms of treatment can be used to modify the tumor microenvironment to liberate tumor antigens and decrease immunosuppression. Chemotherapy and radiotherapy can be used to modulate the tumor microenvironment to enhance immunotherapy.

Malignant cells are susceptible to viral infection and consequent cell death. Virus-induced cell death is endowed with features that are known to stimulate innate and adaptive immune responses. Thus danger signals emitted by cells succumbing to viral infection as well as viral nucleic acids are detected by specific receptors, and tumor cell antigens can be routed to professional antigen-presenting cells. The anticancer immune response triggered by viral infection is frequently insufficient to eradicate malignancy but may be further amplified. For this purpose, transgenes encoding cytokines as co-stimulatory molecules can be genetically engineered into viral vectors. Alternatively, or in addition, it is possible to use monoclonal antibodies that either block inhibitory receptors of immune effector cells, or act as agonists for co-stimulatory receptors. Combined strategies are based on the ignition of a local immune response at the malignant site plus systemic immune boosting. We have recently reported examples of this approach involving the Vaccinia virus or Semliki Forest virus, interleukin-12 and anti-CD137 monoclonal antibodies.

The presence of tumor immune infiltrating cells (TILs), particularly CD8(+) T-cells, is a robust predictor of outcome in patients with colorectal cancer (CRC). We revisited TIL abundance specifically in patients with microsatellite stable (MSS) CRC without evidence of lymph node or metastatic spread. Examination of the density of CD8(+) T-cells in primary tumors in the context of other pro-oncogenic markers was performed to investigate potential regulators of TILs. Two independent cohorts of patients with MSS T2-4N0M0 CRC, enriched for cases with atypical relapse, were investigated. We quantified CD8(+) and CD45RO(+) -TILs, inflammatory markers, NFkBp65, pStat3, Cyclo-oxygenase-2 (COX2) and GRP78 as well as transcription factors (TF), β-catenin and MYB. High CD8(+) TILs correlated with a better relapse-free survival in both cohorts (p = 0.002) with MYB and its target gene, GRP78 being higher in the relapse group (p = 0.001); no difference in pSTAT3 and p65 was observed. A mouse CRC (CT26) model was employed to evaluate the effect of MYB on GRP78 expression as well as T-cell infiltration. MYB over-expressing in CT26 cells increased GRP78 expression and the analysis of tumor-draining lymph nodes adjacent to tumors showed reduced T-cell activation. Furthermore, MYB over-expression reduced the efficacy of anti-PD-1 to modulate CT26 tumor growth. This high MYB and GRP78 show a reciprocal relationship with CD8(+) TILs which may be useful refining the prediction of patient outcome. These data reveal a new immunomodulatory function for MYB suggesting a basis for further development of anti-GRP78 and/or anti-MYB therapies.

Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit. However, the receptor–ligand interactions that critically dictate NK cell function in AML remain undefined. Here, we demonstrate that CD112/CD155 expression is required for DNAM-1-dependent killing of AML cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell lines resulted in failure to stimulate optimal NK cell function. Importantly, isolated clones with low CD112/155 expression were resistant to NK cell killing while those expressing abundant levels of CD112/155 were highly susceptible. Attenuated NK cell killing in the absence of CD112/CD155 originated from decreased NK–target cell conjugation. Furthermore, we reveal by time-lapse microscopy, a significant increase in NK cell ‘failed killing’ in the absence of DNAM-1 ligands. Consequently, NK cells preferentially lysed ligand-expressing cells within heterogeneous populations, driving clonal selection of CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify reduced CD155 expression as a major NK cell escape mechanism in AML and an opportunity for targeted immunotherapy.

In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8+ effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4+ T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.

This commentary provides the authors' perspective on the article "Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice", published in PLoS ONE. It also discusses the caveats of using subcutaneous tumors to model the treatment of human cancers versus orthotopic mouse models that more closely mimic human disease.

There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy.