Macrophages and Metabolism in the Tumor Microenvironment

Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.

The Acidic Tumor Microenvironment as a Driver of Cancer.

Tumor cells constantly interact with their microenvironment, which comprises a variety of immune cells together with endothelial cells and fibroblasts. The composition of the tumor microenvironment (TME) has been shown to influence response to immune checkpoint blockade (ICB). ICB takes advantage of immune cell infiltration in the tumor to reinvigorate an efficacious antitumoral immune response. In addition to tumor cell intrinsic biomarkers, increasing data pinpoint the importance of the TME in guiding patient selection and combination therapies. Here, we review recent efforts in determining how various components of the TME can influence response and resistance to ICB. Although a large body of evidence points to the extent and functional orientation of the T cell infiltrate as important in therapy response, recent studies also confirm a role for other components of the TME, such as B cells, myeloid lineage cells, cancer-associated fibroblasts, and vasculature. If the ultimate goal of curative cancer therapies is to induce a long-term memory T cell response, the other components of the TME may positively or negatively modulate the induction of efficient antitumor immunity. The emergence of novel high-throughput methods for analyzing the TME, including transcriptomics, has allowed tremendous developments in the field, with the expansion of patient cohorts, and the identification of TME-based markers of therapy response. Together, these studies open the possibility of including TME-based markers for selecting patients that are likely to respond to specific therapies, and pave the way to personalized medicine in oncology.

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The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies.

Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.

/pdf/the-role-of-hypoxia-in-the-tumor-microenvironment-and-3efrgc4oyh.pdf

The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment.

Abstract Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy. 

/pdf/hypoxic-microenvironment-in-cancer-molecular-mechanisms-and-2xbbj46h.pdf

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.

/pdf/targeted-hypoxia-reduction-restores-t-cell-infiltration-and-v06awtd4b5.pdf

Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Tumor hypoxia contributes to chemotherapy and radiotherapy resistance, and helps foster metastasis. Hypoxia likely also supports tumor immune resistance by supporting development of suppressive myeloid and T cell populations by activating immunosuppressive signaling pathways in the tumor and stroma, and by creating a metabolically hostile environment for immune effector cells. TH-302 is a hypoxia-specific chemotherapeutic drug which is activated only in the hypoxic cores of tumors and remains harmless in the periphery. We hypothesized that concurrent combination therapy with TH-302 and T cell checkpoint blockade would promote inside-out tumor destruction with the drug killing at the core, releasing antigen, and diminishing suppression, while the antibodies helped expand and protect the T cells activated as a result. In the TRAMP-C2 prostatic adenocarcinoma model, we found that antibody blockade of CTLA-4 and PD-1, used in conjunction with TH-302 administration, promoted tumor rejection in a significantly larger percentage of mice than either therapy alone. The combination therapy promoted uniquely advantageous ratios of effector T cells to MDSC within the prostate cancer microenvironment. This novel combination of immunotherapy and hypoxia-specific chemotherapy has the potential to offer profound anti-tumor responses to a much greater percentage of patients than either chemotherapy or immunotherapy alone with the same or fewer side effects.

Citation Format: Midan Ai, Todd Bartkowiak, Ashvin R. Jaiswal, Krishna Shah, Casey Ager, Beatrisa Lerman, Michael A. Curran. Combination hypoxia-specific chemotherapy and immunotherapy of prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 629. doi:10.1158/1538-7445.AM2014-629

Abstract 629: Combination hypoxia-specific chemotherapy and immunotherapy of prostate cancer

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Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy

Abstract 629: Combination hypoxia-specific chemotherapy and immunotherapy of prostate cancer