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

OncologyOncology Vol 28 No 11
Volume 28
Issue 11

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.

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 ( 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 ( 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.


1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

2. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicenter, randomized, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-12.

3. Drake CG. Visceral metastases and prostate cancer treatment: ‘die hard,’ ‘tough neighborhoods,’ or ‘evil humors’? Oncology (Williston Park). 2014;28:974-80.

4. Akfirat C, Zhang X, Ventura A, et al. Tumour cell survival mechanisms in lethal metastatic prostate cancer differ between bone and soft tissue metastases. J Pathol. 2013;230:291-7.

5. Halabi S, Kelly WK, Zhou H, et al. The site of visceral metastases (mets) to predict overall survival (OS) in castration-resistant prostate cancer (CRPC) patients (pts): a meta-analysis of five phase III trials. J Clin Oncol. 2014;32(suppl 5):abstr 5002.

6. Armstrong AJ, Garrett-Mayer ES, Yang YC, et al. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. 2007;13:6396-403.

7. Goodman OB, Jr, Flaig TW, Molina A, et al. Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:34-9.

8. Gradilone A, Gazzaniga P, Ribuffo D, et al. Survivin, bcl-2, bax, and bcl-X gene expression in sentinel lymph nodes from melanoma patients. J Clin Oncol. 2003;21:306-12.

9. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147-63.

10. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37.

11. Davidsson S, Ohlson AL, Andersson SO, et al. CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer. Mod Pathol. 2013;26:448-55.

12. Liu Y, Saeter T, Vlatkovic L, et al. Dendritic and lymphocytic cell infiltration in prostate carcinoma. Histol Histopathol. 2013;28:1621-8.

13. Liu Y, Vlatkovic L, Saeter T, et al. Is the clinical malignant phenotype of prostate cancer a result of a highly proliferative immune-evasive B7-H3-expressing cell population? Int J Urol. 2012;19:749-56.

14. Holmgaard RB, Zamarin D, Munn DH, et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389-402.

15. Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12:1144-51.

16. Feder-Mengus C, Wyler S, Hudolin T, et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur J Cancer. 2008;44:2266-75.

17. Chapoval AI, Ni J, Lau JS, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2:269-74.

18. Hashiguchi M, Kobori H, Ritprajak P, et al. Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci U S A. 2008;105:10495-500.

19. Hofmeyer KA, Ray A, Zang X. The contrasting role of B7-H3. Proc Natl Acad Sci U S A. 2008;105:10277-8.

20. Manning EA, Ullman JG, Leatherman JM, et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res. 2007;13:3951-9.

21. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632-42.

22. Rini BI, Weinberg V, Fong L, et al. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer. 2006;107:67-74.

23. Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 2012;61:255-63.

24. Shimura S, Yang G, Ebara S, et al. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res. 2000;60:5857-61.

25. Wen SW, Ager EI, Christophi C. Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther. 2013;14:606-13.

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