Mechanisms of Immunotherapy Resistance in mCRPC: Identifying the Enemy on the Visceral Metastatic Battlefield

In a phase III clinical trial, blockade of the cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) inhibitory receptor by ipilimumab led to activation and proliferation of cytotoxic T cells, tumor regression, and clinical benefit in a subset of patients with advanced/metastatic melanoma.[1] The CA184-043 trial was a large phase III trial of ipilimumab vs placebo in patients with post-docetaxel metastatic castration-resistant prostate cancer (mCRPC).[2]

This trial, unfortunately, failed to meet the primary endpoint of overall survival. However, a post-hoc analysis of survival showed that patients without visceral metastases derived significant benefit from ipilimumab as compared with placebo while those with visceral metastases did not. In this issue of ONCOLOGY, Dr. Drake proposes three hypothetical mechanisms of resistance to immunotherapy in the setting of visceral mCRPC.[3]

First is the “Die Hard” hypothesis that visceral metastases differ in biology compared with bone metastases, specifically with respect to antiapoptotic pathways. This hypothesis is supported by the work of Akfirat et al showing greater upregulation of antiapoptotic and prosurvival mediators in soft tissue vs bone metastasis.[4] It is interesting to note that docetaxel[5,6] and abiraterone[7] benefit patients regardless of metastatic site. While these agents may not depend on intact apoptotic machinery to the same extent as immunotherapy, further investigation into the susceptibility of visceral metastases to androgen receptor–targeted and tubulin-targeted therapies is critical to our understanding of this differential response. It is also important to ask why visceral, particularly hepatic, CRPC metastases are resilient to immunologic attack while hepatic melanoma metastases are susceptible to an immunotherapy, despite similar patterns of apoptotic pathway upregulation.[8] It is noteworthy that the liver is a lymphoid organ vested with multiple immunoregulatory mechanisms to allow immunologic tolerance, since it constantly deals with a wide range of antigenic materials received via the blood supply from the intestine and systemic circulation.[9] Thus, one may postulate that cancer cells in the liver may take advantage of these immuneoregulatory mechanisms to evade immunologic attack.

We propose the additional, complementary “Invincible Ironman” hypothesis and pose the question: What protective armor do hepatic metastases have against immune attack? Immune checkpoints, such as B7 homolog 1 (also known as programmed cell death ligand-1 [PD-L1]) confer adaptive resistance in melanoma[10] and other tumor types. While there are limited data available regarding the immunophenotypes of hepatic CRPC metastases, analysis of primary prostate cancer tumors suggests that lethal tumors are often characterized by upregulation of immune checkpoint molecules in an immunosuppressive microenvironment.[11-13] One may postulate that immune checkpoints protect CRPC hepatic metastases against cytotoxic T cells activated by anti–CTLA-4 blockade or therapeutic cancer vaccines. For instance, one well-documented immune resistance mechanism to anti–CTLA-4 blockade is the indoleamine 2,3-dioxygenase (IDO) pathway. In preclinical experiments,[14] combination anti–CTLA-4 blockade and IDO inhibition showed synergistic antitumor activity even in poorly immunogenic tumors. High expression of IDO has been also described in colon cancer hepatic metastases[15] and in prostate cancers.[16] An IDO inhibitor, indoximod, is being investigated in a phase II study combined with sipuleucel-T in patients with mCRPC (ClinicalTrials.gov Identifier: NCT01560923).

B7 homolog 3 (B7-H3 ) was first reported to be a costimulatory molecule by Dr. Chen’s group.[17] Additional evidence suggests that B7-H3 can act as both costimulatory and coinhibitory factors, depending on the ligand binding.[18,19] High expression of B7-H3 is associated with higher pathologic stage, Gleason score, and Ki-67 proliferative index in prostate cancer-all factors that correlate with risk of progression.[13] The first-in-class antibody against human B7-H3, the humanized monoclonal antibody MGA271, is being evaluated in a phase I study in patients with solid tumors, including mCRPC (ClinicalTrials.gov Identifier: NCT01391143).

Complementing the “Tough Neighborhood” hypothesis, we propose the “Bad Boys” hypothesis. As Dr. Drake notes, upregulation of angiogenic pathways in hepatic CRPC metastases may contribute to immunosuppression by delaying dendritic cell maturation and migration and thus impeding the adaptive immune response.[20] Several clinical trials have evaluated immunotherapy in combination with antiangiogenic agents to test this theory,[21,22] and more studies are ongoing. In addition, the “Tough Neighborhood” of the tumor microenvironment is infested with immunosuppressive cells, including regulatory T cells,[11] myeloid-derived suppressor cells,[23] and tumor-associated macrophages[24]-the so-called “Bad Boys,” because their presence correlates with poor prognosis in men with prostate cancer. While quantification of these factors within hepatic CRPC metastases has not been published, such studies would be of interest, as these immunosuppressive cells have been shown to ward off cytotoxic T cells by producing “Evil Humors.”[3]

Finally, the “Good Neighbors Gone Bad” hypothesis may be entertained. Kupffer cells, resident liver macrophages long known as “good neighbors” due to their critical role in liver homeostasis, may in fact be mediators of the aggressive biology of hepatic metastases. Evidence suggests that Kupffer cells have both stimulatory and inhibitory functions during tumor development. In an orthotopic murine model of colorectal cancer liver metastases, Wen et al showed that while Kupffer cell depletion in the early stages of tumor growth was associated with increased tumor burden, Kupffer cell depletion at the late stage of tumor growth decreased liver tumor load compared with nondepleted animals.[25] Kupffer cell depletion at the late stage was associated with increased tumor infiltration of CD3+ T cells and inducible nitric oxide synthase–expressing infiltrating cells. This observation may have relevance to the lack of therapeutic effect of ipilimumab observed in patients with hepatic CRPC metastasis in the CA184-043 study.[2] When the burden of hepatic metastases is minimal, Kupffer cells exert cytotoxicity, whereas when the burden is high, it appears that Kupffer cells not only lose cytotoxic function, but may in fact promote progression of hepatic metastasis.

In conclusion, clinical trial results to date show that men with visceral CRPC metastases do not benefit from ipilimumab, while their counterparts with bone- or node-only metastases do. This suggests that visceral metastases should be a stratification factor for future immunotherapy clinical trials. The “Die Hard,” “Tough Neighborhood,” and “Evil Humors” hypotheses suggest plausible mechanisms of T-cell immunotherapy resistance in aggressive mCRPC. We propose the complementary “Ironman,” “Bad Boys,” and “Good Neighbors Gone Bad” hypotheses. The testing of all these hypotheses will enhance our understanding of mechanisms of immune escape in mCRPC and, it is hoped, suggest novel immunotherapeutic approaches to this disease.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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