Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis and increases anti-tumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells.
Purpose
To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (IM; CCR2+/CD14+) as immunotherapeutic targets in the treatment of pancreatic cancer (PC).
Experimental Design
Survival analysis was performed to determine if the prevalence of pre-operative blood monocytes correlates with survival in PC patients following tumor resection. IM prevalence in the blood and bone marrow of PC patients and controls was compared. The immunosuppressive properties of IM and macrophages in the blood and tumors, respectively, of PC patients were assessed. CCL2 expression by human PC tumors was compared to normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine PC.
Results
Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in PC patients with resected tumors. IM are increased in the blood and decreased in the bone marrow of PC patients compared to controls. An increased ratio of IM in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human PC produces CCL2, and immunosuppressive CCR2+ macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes IM and macrophages from the primary tumor and premetastatic liver resulting in enhanced anti-tumor immunity, decreased tumor growth, and reduced metastasis.
Conclusions
IM recruitment is critical to PC progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.
Extracapsular extension in squamous cell carcinoma nodal metastases
usually predicts worse outcome. However, there are no standard histologic
grading criteria for extracapsular extension, and there have been few studies on
oropharyngeal squamous cell carcinoma alone. We studied the extent of
extracapsular extension utilizing a novel grading system and correlated grades
with outcomes while controlling for p16 status. A cohort of surgically treated
oropharyngeal squamous cell carcinoma cases were reviewed and metastases graded
as 0 (within substance of node), 1 (filling subcapsular sinus with thickened
capsule/pseudocapsule, but no irregular peripheral extension), 2 (≤1mm
beyond capsule), 3 (>1mm beyond capsule), or 4 (no residual nodal tissue
or architecture; ‘soft tissue metastasis’). There were 101
cases, for which p16 was positive in 90 (89%). Extracapsular extension
grades did not correlate with nodal size (P = 0.28) or p16
status (P = 0.8). In follow up, 10 patients (10%) had
disease recurrence with only 3 of 64 (5%) grade 0–3 cases and 7
of 37 (19%) with grade 4 recurring (P = 0.04). Grade 4
extracapsular extension was associated with poorer survival (P
< 0.01). However, grade 4 extracapsular extension correlated with higher
T-stage (P = 0.02), and in multivariate analysis, was not
significantly associated with poorer overall (P = 0.14)
disease-free (P = 0.2), or disease-specific survival
(P = 0.09). The impact of extracapsular extension in nodal
metastases is limited in oropharyngeal squamous cell carcinoma. Only
extracapsular extension grade 4 associates with poorer outcomes, but not
independently of T-stage and other variables.
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