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. 2018 Sep 6;7(12):e1500108.
doi: 10.1080/2162402X.2018.1500108. eCollection 2018.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Russell Maxwell  1   2 , Andrew S Luksik  1 , Tomas Garzon-Muvdi  1 , Alice L Hung  1 , Eileen S Kim  1 , Adela Wu  1 , Yuanxuan Xia  1 , Zineb Belcaid  1 , Noah Gorelick  1 , John Choi  1 , Debebe Theodros  1 , Christopher M Jackson  1 , Dimitrios Mathios  1 , Xiaobu Ye  1 , Phuoc T Tran  2 , Kristin J Redmond  2 , Henry Brem  1 , Drew M Pardoll  3 , Lawrence R Kleinberg  2 , Michael Lim  1
Affiliations

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Russell Maxwell et al. Oncoimmunology. .

Abstract

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

Keywords: PD-1; brain tumor; central nervous system; colon adenocarcinoma; corticosteroid; dexamethasone; glioma; immunotherapy.

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Figures

Figure 1.
Figure 1.
Dexamethasone impairs colon adenocarcinoma MC38 flank tumor growth patterns in mice administered anti-PD-1 therapy. (A) Schematic diagram of experimental design and treatment paradigm: Female C57BL/6J mice (N = 64) were subcutaneously inoculated with 500,000 colon adenocarcinoma MC38 cells in the right flank (day 0) and monitored for tumor growth. Once tumors were palpable, mice were randomized (8 mice/group) to ensure tumor burden was equal amongst the groups (day 8). Mice were administered anti-PD-1 antibody (200 ug/dose, 10 mg/kg, intraperitoneal injection) on days 8, 10, and 12; concurrent dexamethasone (200 ug/dose, 10 mg/kg, intraperitoneal injection) on days 8 through 12 (Dex-1); sequential dexamethasone on days 13 through 17 (Dex-2); and/or continuous dexamethasone from days 8 (randomization date) through 36 (4 weeks) with taper (Dex-Cont). (B) Individual tumor volume growth curves by treatment group: Mice that did not receive anti-PD-1 therapy had continued exponential tumor growth, resulting in no tumor-free mice (0.0%). Anti-PD-1 monotherapy resulted in 50.0% tumor-free mice. However, combination anti-PD-1 and dexamethasone therapy appeared to disrupt this trend (% tumor-free: anti-PD-1 + Dex-1, 12.5%; anti-PD-1 + Dex-2, 12.5%; anti-PD-1 + Dex-Cont, 0.0%). (C) Anti-PD-1 monotherapy resulted in a significantly prolonged tumor doubling time compared to untreated control mice. This effect was abrogated by dexamethasone therapy. (D) and (E) Tumor volume growth patterns between the groups: Anti-PD-1 therapy, regardless of dexamethasone treatment, delayed the early growth of tumors compared to untreated control mice on day 28. However, this effect was abrogated with dexamethasone treatment long-term on day 38. Means were compared using one-way ANOVA and Dunnett’s multiple comparisons test (untreated control and anti-PD-1 alone arms were the designated reference groups on days 28 and 38, respectively). ns, P > 0.05; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. If no asterisks are shown in (C), statistical analyzes yielded non-significant P-values.
Figure 2.
Figure 2.
Dexamethasone alone or combined with anti-PD-1 therapy significantly alters peripheral T cell compartments in mice bearing colon adenocarcinoma MC38 flank tumors. (A) Timeline of blood draws relative to treatment schedule in MC38 flank tumor experiment (N = 64, 8 mice/group): Blood was collected from the retro-orbital venous plexus of each mouse on days 8 (pre-treatment), 15 (shortly after anti-PD-1 therapy completion), and 27 (long time after anti-PD-1 therapy). Depicted are absolute numbers of (B) CD4+, (C) CD8+, (D) CD4+ FOXP3+ regulatory T cells (Treg), and (E) CD8/Treg ratios in peripheral blood by treatment group. Means were compared within each group using one-way ANOVA and Tukey’s multiple comparisons test. Dexamethasone treatment, either alone or in combination with anti-PD-1 therapy, resulted in persistent reductions within CD4+, CD8+, and Treg compartments. Anti-PD-1 therapy improved peripheral CD8/Treg ratios. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. If no asterisks are shown, statistical analyzes yielded non-significant P-values.
Figure 3.
Figure 3.
Peripheral CD8/Treg ratio changes correlate with tumor regressions and long-term responses in mice bearing colon adenocarcinoma MC38 flank tumors given anti-PD-1 therapy with or without dexamethasone. (A) Waterfall plot (n = 58) of fold tumor volume changes from day 12 (immediately after last anti-PD-1 dose) to day 28 (approximately 2 weeks following anti-PD-1 treatment) overlaid with scatter plot of peripheral CD8/Treg ratio changes from day 15 to 27 (open circles): As visualized, mice treated with anti-PD-1 therapy alone represented the majority of mice with tumor regressions (n = 8). Two mice within the anti-PD-1 + Dex-2 group (gray open circles, labeled #1–2) were found to have partial responses, which were then followed by progressive disease. Six mice (purple open circles, labeled #3–8, anti-PD-1: n = 4, anti-PD-1 + Dex-1: n = 1, anti-PD-1 + Dex-2: n = 1) had complete responses, which were durable. Additionally, tumor volume changes were inversely related to CD8/Treg ratio changes (slope = −1.20, R2 = 0.23, P < 0.0001). (B) Dynamics between tumor volume and peripheral CD8/Treg ratio changes from baseline in untreated controls (top left panel), partial responders followed by progressive disease (top right panel), and complete responders (bottom panel): As visualized, tumor growth typically coincided with drops in CD8/Treg ratios in control mice. However, complete responders had a significant increase in their CD8/Treg ratios, which correlated with tumor regressions. The partial responders who ultimately had PD failed to display this trend. (C) In all mice administered anti-PD-1 therapy (n = 32), regardless of dexamethasone treatment, those with ≥ 20% change in peripheral CD8/Treg ratios had significantly slower tumor growths compared to those with < 20% changes. (D) Moreover, in all mice treated with anti-PD-1 therapy (n = 32), long-term responders (LTR) had higher peripheral CD8/Treg ratio changes compared to those with progressive disease (P = 0.0080). Means for (C) and (D) were compared using Welch’s t-test assuming unequal variances. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. If no asterisks are shown, statistical analyzes yielded non-significant P-values.
Figure 4.
Figure 4.
Dexamethasone does not abrogate the survival benefit conferred by anti-PD-1 therapy in intracranial glioma-bearing mice. (A) Schematic diagram of experimental design and treatment paradigm: Female C57BL/6J mice (n = 80) were intracranially implanted with 130,000 luciferase-expressing glioma (GL261-Luc) cells within the left striatum and monitored for tumor growth by bioluminescence imaging using an In Vivo Imaging System (IVIS). On day 7, mice were randomized (10 mice/group) to ensure tumor burden was equal amongst the groups. Mice were administered anti-PD-1 antibody (200 ug/dose, 10 mg/kg intraperitoneal injection) on days 10, 12, and 14; concurrent dexamethasone (200 ug/dose, 10 mg/kg, intraperitoneal injection) on days 10 through 14 (Dex-1); sequential dexamethasone on days 15 through 19 (Dex-2); and/or continuous dexamethasone from days 7 (randomization date) through 35 (4 weeks) with taper (Dex-Cont). (B) Dex-1, (C) Dex-2, and (D) Dex-Cont sub-group analyzes demonstrate combination therapy with dexamethasone does not significantly impair the survival advantage conferred by PD-1 blockade in mice harboring intracranial GL261-Luc tumors. ns, P > 0.05; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
Figure 5.
Figure 5.
Dexamethasone alone or combined with anti-PD-1 therapy significantly alters peripheral T cell compartments in mice bearing intracranial glioma tumors. (A) Timeline of blood draws relative to treatment schedule in the intracranial GL261-Luc experiment (N = 80, 10 mice/group): Blood was collected from the retro-orbital venous plexus of each mouse on days 19 and 27. Depicted are absolute numbers of (B) CD4+, (C) CD8+, (D) CD4+ FOXP3+ regulatory T cells (Treg), and (E) CD8/Treg ratios in peripheral blood by treatment group. Dexamethasone treatment, either alone or in combination with anti-PD-1 therapy, resulted in persistent reductions within CD4+, CD8+, and Treg compartments. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. If no asterisks are shown, statistical analyzes yielded non-significant P-values.
Figure 6.
Figure 6.
Anti-PD-1-mediated antitumor immune responses are maintained during combination dexamethasone therapy, as witnessed in tumor-draining lymph nodes (TDLN) of glioma-bearing mice. Representative flow cytometry scatter plots of CD4+ vs. CD8+ surface markers (gated on live CD3+ T cells) and their aggregate analyzes derived from TDLN (harvested on day 19, 5 mice/group): Compared to untreated control mice, dexamethasone monotherapy substantially reduced CD4+ and CD8+ T cell numbers in TDLN. However, these levels were maintained in mice receiving combination anti-PD-1 and dexamethasone therapy. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. If no asterisks are shown, statistical analyzes yielded non-significant P-values.
Figure 7.
Figure 7.
Tumor-specific immunologic memory is grossly preserved in long-term responders treated with combination anti-PD-1 and dexamethasone therapy. Briefly, long-term survivors along with naïve control mice (n = 5) underwent tumor rechallenge by implanting 260,000 GL261-Luc cells within the contralateral cerebral hemisphere (day 0). Tumor burden was monitored via bioluminescence using an In Vivo Imaging System (IVIS). (A) IVIS imaging results on days 7 and 21 following tumor rechallenge: On day 7, all naïve control mice established tumors, while none of the long-term survivors had tumors. However, 1 of 6 mice (17%) in the anti-PD-1 + Dex-Cont group was found to have a tumor on day 21. (C) Survival analyzes of tumor rechallenge experiment: Except for the naïve controls and the one anti-PD-1 + Dex-Cont mouse with tumor on day 21, all other mice had prolonged survival following tumor rechallenge, suggesting intact immunologic memory.
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