TY - JOUR
T1 - Targeting PIM kinase with PD1 inhibition improves immunotherapeutic antitumor t-cell response
AU - Chatterjee, Shilpak
AU - Chakraborty, Paramita
AU - Daenthanasanmak, Anusara
AU - Iamsawat, Supinya
AU - Andrejeva, Gabriela
AU - Luevano, Libia A.
AU - Wolf, Melissa
AU - Baliga, Uday
AU - Krieg, Carsten
AU - Beeson, Craig C.
AU - Mehrotra, Meenal
AU - Hill, Elizabeth G.
AU - Rathmell, Jeffery C.
AU - Yu, Xue Zhong
AU - Kraft, Andrew S.
AU - Mehrotra, Shikhar
N1 - Funding Information:
The work was supported in part by NIH grants R21CA137725, R01CA138930, and P01CA154778 subcontract (to S. Mehrotra). Support from Hollings Cancer Center Shared Resources (partly supported by P30 CA138313) at MUSC is also acknowledged. This study was also supported by University of Arizona Cancer Center support grant P30CA023074, NIH award R01CA173200, and DOD award W81XWH-12-1-0560 (to A.S. Kraft).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Purpose: Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor. Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100-reac-tive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both. Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upre-gulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination. Conclusions: This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.
AB - Purpose: Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor. Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100-reac-tive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both. Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upre-gulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination. Conclusions: This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.
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U2 - 10.1158/1078-0432.CCR-18-0706
DO - 10.1158/1078-0432.CCR-18-0706
M3 - Article
C2 - 30327305
AN - SCOPUS:85060939181
VL - 25
SP - 1036
EP - 1049
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 3
ER -