Seminar Article
The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer

https://doi.org/10.1016/j.urolonc.2018.10.011Get rights and content

Abstract

Immunotherapy—particularly immune checkpoint blockade—has seen great success in many tumor types. However, checkpoint-based therapies have not demonstrated high levels of success in prostate cancer, and there is much to be learned from both the successes and failures of these treatments. Here we review the evidence that composition of infiltrating immune cells in the tumor microenvironment is fundamental to the response to immunotherapy. Additionally, we discuss the emerging idea that the organization of these immune cells may also be crucial to this response. In prostate cancer, the composition and organization of the tumor immune microenvironment are preeminent topics of discussion and areas of important future investigation.

Introduction

Prostate cancer is the most common cancer diagnosis made in men today, and while surgery, radiation therapy, and expectant management strategies boast encouraging survival outlooks (with the 10-year risk of death from prostate cancer ranging from 3% to 18%, depending on risk group), therapeutic advances are still needed, especially for metastatic and hormone refractory patients [1,2]. Accordingly, there is hope that immunotherapy could fill this space—to be an effective therapeutic option for castrate resistant disease—or even become an earlier option, perhaps mitigating the undesired side effects of currently employed therapies. Here, we will review the successes and failures of using immunotherapy to treat prostate cancer. We discuss the mechanisms associated with immunotherapy response in other cancers and why prostate cancer may be more refractory to this approach.

Section snippets

Lessons and successes in prostate cancer immunotherapy

Since the Food and Drug Administration (FDA) approval of Sipuleucel-T for prostate cancer and of immune checkpoint therapies for melanoma, trials of immunotherapies have proliferated across a multitude of tumor types. The greatest success of immune checkpoint therapies was found in densely immune-infiltrated "hot" tumors, such as melanoma [3,4]. However, the trials conducted in immunologically "cold" (i.e., poorly immune infiltrated) tumors, such as prostate cancer, did not match the impressive

The composition of the immune microenvironment is prognostically valuable and functionally important

The tumor microenvironment (TME) includes numerous immune cell subsets, which are crucial in the antitumor immune response. Depending on the organization, location, and phenotype of the cells, they can either promote or impede the antitumor immune response (Fig. 1). In order to understand how the immune system is responding to different tumors, the cell populations must be analyzed and studied in order to understand the way these populations interact. The fundamental cell populations in the

Organization in the immune microenvironment

The association between tumor T-cell infiltration and improved survival and response to immunotherapy has resulted in the categorization of various tumors as either immunologically ‘hot’ or ‘cold.’ In addition, others have further delineated phenotypic categories of immune infiltration—immune-inflamed, immune-excluded, and immune-desert—in attempts to explain the variation seen clinical behavior [86]. Immune-inflamed tumors are generally thought to carry a positive prognosis, while

Future perspective

Here we have reviewed the use of immunotherapy in prostate cancer and the mechanisms that support responses to immunotherapy. Additionally, we have specified potential explanations for why immunotherapy has delivered lower response rates than in some other cancers. Based on the evidence presented here, it is clear that immune infiltration and organization in the TME—such as in the formation of TLS—plays an important role in antitumor immunity and in the response to immunotherapy. Specifically,

References (127)

  • L Chen et al.

    Molecular mechanisms of T cell co-stimulation and co-inhibition

    Nat Rev Immunol

    (2013)
  • S Jung et al.

    In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens

    Immunity

    (2002)
  • M Haniffa et al.

    Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells

    Immunity

    (2012)
  • EW Roberts et al.

    Critical role for CD103<sup>+</sup>/CD141<sup>+</sup>dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma

    Cancer Cell

    (2016)
  • ML Broz et al.

    Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity

    Cancer Cell

    (2014)
  • BZ Qian et al.

    Macrophage diversity enhances tumor progression and metastasis

    Cell

    (2010)
  • BA Anthony et al.

    Regulation of hematopoietic stem cells by bone marrow stromal cells

    Trends Immunol

    (2014)
  • L Yang et al.

    TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

    Trends Immunol

    (2010)
  • TF Gajewski et al.

    Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment

    Curr Opin Immunol

    (2013)
  • TF Gajewski

    The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment

    Semin Oncol

    (2015)
  • M Bajenoff et al.

    Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes

    Immunity

    (2006)
  • MS Litwin et al.

    The diagnosis and treatment of prostate cancer: a review

    JAMA

    (2017)
  • TJ Daskivich et al.

    Effect of age, tumor risk, and comorbidity on competing risks for survival in a U.S. population-based cohort of men with prostate cancer

    Ann Intern Med

    (2013)
  • CK Park et al.

    Clinicopathological significance of intratumoral and peritumoral lymphocytes and lymphocyte score based on the histologic subtypes of cutaneous melanoma

    Oncotarget

    (2017)
  • G Saldanha et al.

    A novel numerical scoring system for melanoma tumor-infiltrating lymphocytes has better prognostic value than standard scoring

    Am J Surg Pathol

    (2017)
  • TM Beer et al.

    Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer

    J Clin Oncol

    (2017)
  • F Fakhrejahani et al.

    Avelumab in metastatic castration-resistant prostate cancer (mCRPC)

    J Clin Oncol

    (2017)
  • JD Wolchok et al.

    Nivolumab plus Ipilimumab in Advanced Melanoma

    N Engl J Med

    (2013)
  • JD Wolchok et al.

    Overall survival with combined nivolumab and ipilimumab in advanced melanoma

    N Engl J Med

    (2017)
  • M Reck et al.

    Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer

    N Engl J Med

    (2016)
  • Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. Nivolumab in patients with metastatic DNA...
  • Overman MJ, Lonardi S, Wong KYM, Lenz H-J, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus...
  • B Escudier et al.

    LBA5CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups

    Ann Oncol

    (2017)
  • I Silvestri et al.

    A perspective of immunotherapy for prostate cancer

    Cancers (Basel)

    (2016)
  • EJ Small et al.

    A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer

    Clin Cancer Res

    (2007)
  • L Fong et al.

    Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF

    Cancer Res

    (2009)
  • DG McNeel et al.

    Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer

    Cancer Immunol Immunother

    (2012)
  • A Hansen et al.

    Pembrolizumab for patients with advanced prostate adenocarcinoma: preliminary results from the KEYNOTE-028 study

    Ann Oncol

    (2016)
  • J Higa et al.

    Pembrolizumab for recurrent or advanced prostate cancer

    J Clin Oncol

    (2018)
  • K Boudadi et al.

    Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC)

    J Clin Oncol

    (2017)
  • JSD Bono et al.

    KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC)

    J Clin Oncol

    (2018)
  • JN Graff et al.

    Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

    Oncotarget

    (2016)
  • PC Tumeh et al.

    PD-1 blockade induces responses by inhibiting adaptive immune resistance

    Nature

    (2014)
  • MC Dallos et al.

    Blocking PD-1/PD-L1 in genitourinary malignancies: to immunity and beyond

    Cancer Journal (Sudbury, Mass)

    (2018)
  • F Karzai et al.

    Combination of PDL-1 and PARP inhibition in an unselected population with metastatic castrate-resistant prostate cancer (mCRPC)

    J Clin Oncol

    (2017)
  • J-M Lee et al.

    Checkpoint and PARP inhibitors, for whom and when

    Oncotarget

    (2017)
  • N McGranahan et al.

    Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

    Science

    (2016)
  • NA Rizvi et al.

    Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

    Science

    (2015)
  • ZR Chalmers et al.

    Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

    Genome Med

    (2017)
  • PW Kantoff et al.

    Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer

    J Clin Oncol

    (2010)
  • View full text