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Pancreatic ductal adenocarcinoma (PDAC) is projected to surpass breast, prostate and colorectal cancers to become the second leading cause of cancer-related death by 2030.1 Despite recent advances in combination chemotherapies, the prognosis remains appallingly poor. Immunotherapeutic approaches using checkpoint inhibitors that have been established as novel pillar of cancer therapy for several other tumour entities have largely failed to improve survival in pancreatic cancer when used as single agents.2 Increasing preclinical and clinical evidence suggests that the immunosuppressive tumour microenvironment (TME) in pancreatic cancer, comprising up to 90% of the tumour volume, functions as an important mediator of therapy resistance and might be responsible for the failure of immunotherapy. Several molecular mechanisms have been identified which enhance the immunosuppressive micromilieu, among them upregulation of inhibitory signalling molecules such as PDL1, CTLA4 and LAG3 or key metabolic enzymes suppressing the antitumorous immune cell function. In addition, tumour-infiltrating bone marrow-derived myeloid cells including tumour-associated macrophages (TAM) and neutrophils (TAN) have been recognised as important mediators of immune evasion.3 These myeloid cells are recruited from the bone marrow to the site of the tumour by distinct chemokine pathways co-opted by the tumour cells to facilitate myeloid cell attraction. In particular, the role of TAN has recently attracted increasing interest after numerous reports have identified elevated numbers of neutrophils both in the circulation (measured as neutrophil-to-lymphocyte ratio) and in the tumour tissue (defined as TAN) as poor prognostic markers.4 In line with these findings, mild therapy-induced neutropenia has been associated with longer survival as demonstrated for patients with advanced non-small cell lung cancer.5
In Gut, Nywening and coworkers focused on both CXCR2+ neutrophils (TAN) and CCR2+ macrophages (TAM), which can be targeted by small molecule CCR2 (CCR2i) and CXCR2 (CXCR2i) inhibitors. The authors report that elevated levels of CXCR2+ TAN in patients with PDAC correlate with poor prognosis. Moreover, patients receiving CCR2i to target TAM showed increased numbers of tumour-infiltrating CXCR2+ TAN. Compatible with this, depletion of either CXCR2+ TAN or CCR2+ TAM in an orthotopic PDAC model resulted in a compensatory response of the alternative myeloid subset, which was associated with upregulation of the respective chemokine milieu. The compensatory reaction was overcome by combined CCR2i and CXCR2i administration, which augmented antitumour immunity and improved response to chemotherapy. These data suggest that dual targeting of CCR2+ TAM and CXCR2+ TAN is superior to either strategy alone.6
The paper in this issue provides clear evidence for combination targeting of the myeloid compartment. In addition to the CCR2 and CXCR2 inhibitors used in this study, several other compounds are available and are being tested in clinical trials to target TAM and TAN populations, respectively. TAM-directed approaches include antibodies or small molecule inhibitors against colony-stimulating-factor-1 receptor (CSF1R), the chemotherapeutic agent trabectidin7 and bisphosphonates such as zoledronate that induce apoptosis of phagocytic myeloid cells.8 Therapeutic targeting of TAN appears to be more challenging, given the increased risk of infections which may occur on decreased neutrophil numbers. Besides CXCR2 inhibition used in this study, several signalling inhibitors or antibodies have been described as modulators of TAN migration and infiltration including the multikinase inhibitor sunitinib, the phosphodiesterase (PDE) inhibitor tadalafil and neutralising anti-interleukin 17 antibodies.5
Interestingly, the authors showed that combined targeting of CCR2+ TAM and CXCR2+ TAN resulted in a significantly greater influx of CD8+ tumour-infiltrating lymphocytes compared with either TAM or TAN targeting alone. In line with this, immunosuppressive FoxP3+, CD25+ regulatory T cells infiltrates were markedly decreased.6 Based on this increased effector-to-suppressor cell ratio in orthotopically implanted syngenic PDAC tumours following treatment with either CCR2i or CXCR2i, the authors performed CD8 depletion studies which showed that the therapeutic efficacy of myeloid blockade is lost in the absence of CD8+ lymphocytes.
These data provide a strong rationale for future studies combining myeloid-targeting with T cell-targeting approaches including checkpoint inhibition. Recent findings revealed that TAM play also an important role when targeting the PD1–PDL1 axis: Arlauckas et al showed that macrophages can remove anti-PD1 antibodies from T cells,9 thereby blunting therapeutic efficacy and representing a potential TAM-mediated mechanism of resistance to checkpoint inhibition. It might be speculated that other phagocytic cells including TAN might well be capable of acting in a similar manner. Therefore, a multitargeting approach involving TAM and TAN-inhibition simultaneously or sequentially with checkpoint inhibition might represent a promising therapeutic avenue to overcome primary or secondary resistance to checkpoint inhibitors. It remains to be elucidated if safety and potential side effects of this combined approach will be manageable to allow further clinical testing.
In this study, the authors used FOLFIRINOX as chemotherapy backbone for their CXCR2 and CCR2 inhibitor studies. It remains to be determined if this regimen proves to be the optimal combination partner when simultaneously targeting the myeloid compartment. Regulatory T cells can be further diminished by gemcitabine. In contrast, paclitaxel and 5-FU have been reported to induce apoptosis primarily in myeloid-derived suppressor cells (MDSC), another immunosuppressive myeloid population with features partly overlapping with TAN.10 Clinical trials are warranted to evaluate the impact of different chemotherapy combination partners.
Irradiation combined with myeloid targeting is another therapeutic avenue with great clinical potential. Local irradiation of tumour cells leads to release of tumour antigens, thereby facilitating a specific immune response, but also induces severe damage to the tumour vasculature.10 Following irradiation, TAMs as the primary tumour-resident population of phagocytes promote early endothelial regrowth and restoration of the vasculature by secreting VEGF and other proangiogenic mediators.11 Accumulating preclinical evidence suggests that irradiation combined with targeting TAM leads to decreased angiogenesis, tumour progression and metastasis formation.11 It might be hypothesised that simultaneous targeting of TAM and TAN even further enhances synergy with radiation therapy.
Taken together, the study presented by Nywening et al 6 and coworkers provides a strong rationale for combined targeting of several myeloid populations and sets the stage for testing combined approaches targeting both innate and adaptive immune responses to overcome resistance to established antitumour therapies in pancreatic cancer and other solid tumours.
Contributors PM and SK drafted and wrote this commentary.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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