Abstract:Summary
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fas… Show more
“…These results confirm that starvation can mediate immunostimulatory effects. 9,19,20 However, they do not resolve the question whether autophagy and its modulation by DMKG impact the cancer cells or the immune system of the host.10.1080/2162402X.2018.1498285-F0001Figure 1. Nutrient deprivation improves tumor vaccination efficacy in an autophagy dependent manner. (A) .…”
Section: Resultsmentioning
confidence: 99%
“…3,19 However, the possible contribution of autophagy in immune effectors has not been studied in this kind of system. We therefore implanted autophagy-competent MCA205 cells into autophagy-competent syngeneic wild type (WT) C57Bl/6 (Figure 2A) or autophagy-deficient hosts such as autophagy related gene 4b ( Atg4b −/- ) (Figure 2B) or Beclin 1 ( Becn1 +/- ) mice (Figure 2C).…”
Section: Resultsmentioning
confidence: 99%
“…30 In the context of cancer, autophagy induction may have oncopreventive and improve therapeutic outcome after chemotherapy effects. 18,19,31–33 In addition, starvation, which is one of the best-known inducers of autophagy, increases the resistance of mice against the toxic effects of anthracycline-based chemotherapy at the same time that it improves tumor growth reduction. 20,34 This autophagy- or starvation-mediated improvement of chemotherapeutic responses has been attributed to an increase in anticancer immunity.…”
Section: Resultsmentioning
confidence: 99%
“…20,34 This autophagy- or starvation-mediated improvement of chemotherapeutic responses has been attributed to an increase in anticancer immunity. 19,20 …”
Section: Resultsmentioning
confidence: 99%
“…3,19,35 Here, we investigated whether partial effects in autophagy conferred by haploinsufficiency in Becn1 or knockout of Atg4b in the host would compromise the chemotherapy-induced anticancer immune response leading to tumor growth reduction after MTX injection. Apparently such partial autophagy defects do not cause a major immunosuppressive effect, supporting the idea that autophagy in the tumor cells (rather than autophagy in immune effectors) is relevant to the therapeutic outcome of immunogenic chemotherapy.…”
The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.
“…These results confirm that starvation can mediate immunostimulatory effects. 9,19,20 However, they do not resolve the question whether autophagy and its modulation by DMKG impact the cancer cells or the immune system of the host.10.1080/2162402X.2018.1498285-F0001Figure 1. Nutrient deprivation improves tumor vaccination efficacy in an autophagy dependent manner. (A) .…”
Section: Resultsmentioning
confidence: 99%
“…3,19 However, the possible contribution of autophagy in immune effectors has not been studied in this kind of system. We therefore implanted autophagy-competent MCA205 cells into autophagy-competent syngeneic wild type (WT) C57Bl/6 (Figure 2A) or autophagy-deficient hosts such as autophagy related gene 4b ( Atg4b −/- ) (Figure 2B) or Beclin 1 ( Becn1 +/- ) mice (Figure 2C).…”
Section: Resultsmentioning
confidence: 99%
“…30 In the context of cancer, autophagy induction may have oncopreventive and improve therapeutic outcome after chemotherapy effects. 18,19,31–33 In addition, starvation, which is one of the best-known inducers of autophagy, increases the resistance of mice against the toxic effects of anthracycline-based chemotherapy at the same time that it improves tumor growth reduction. 20,34 This autophagy- or starvation-mediated improvement of chemotherapeutic responses has been attributed to an increase in anticancer immunity.…”
Section: Resultsmentioning
confidence: 99%
“…20,34 This autophagy- or starvation-mediated improvement of chemotherapeutic responses has been attributed to an increase in anticancer immunity. 19,20 …”
Section: Resultsmentioning
confidence: 99%
“…3,19,35 Here, we investigated whether partial effects in autophagy conferred by haploinsufficiency in Becn1 or knockout of Atg4b in the host would compromise the chemotherapy-induced anticancer immune response leading to tumor growth reduction after MTX injection. Apparently such partial autophagy defects do not cause a major immunosuppressive effect, supporting the idea that autophagy in the tumor cells (rather than autophagy in immune effectors) is relevant to the therapeutic outcome of immunogenic chemotherapy.…”
The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.
Pancreatic cancer is a lethal disease with limited effective treatments. A deeper understanding of its molecular mechanisms is crucial to reduce incidence and mortality. Epidemiological evidence suggests a link between diet and disease risk, though dietary recommendations for at‐risk individuals remain debated. Here, we propose that cell‐intrinsic nutrient sensing pathways respond to specific diet‐derived cues to facilitate oncogenic transformation of pancreatic epithelial cells. This review explores how diet influences pancreatic cancer predisposition through nutrient sensing and downstream consequences for (pre‐)cancer cell biology. We also examine experimental evidence connecting specific food intake to pancreatic cancer progression, highlighting nutrient sensing as a promising target for therapeutic development to mitigate disease risk.
Adenosinergic axis, an innate negative feedback mechanism known as converting adenosine triphosphate (ATP) to adenosine by ectonucleotidases CD39 and CD73, reverses the ATP‐mobilized immunogenic tumor microenvironment (TME) to an immunosuppressive TME caused by adenosine, incapacitating various immune cells (especially effector T cells) in tumor elimination. Herein, for the first time, an injectable hydrogel strategy to reshape the adenosinergic axis by metabolizing adenosine into the immunopotentiator compound inosine is reported for realizing a potent cancer therapy. The solution of adenosine deaminase (ADA), doxorubicin (DOX), benzene‐1,2,3‐tricarboxylic acid (BTC), and sodium alginate gelatinizes in situ in TME, results in an immunogenic niche reshaping the adenosinergic axis. The synergistic cooperation of DOX and BTC boosts ATP induction accompanied by a tumoricidal effect. Simultaneously, ADA catalyzed adenosine into inosine, not only regulating the accumulation of adenosine but also changing it into an immunopotentiator. This strategy possesses the advantage of narrowing the adenosine pool, enriching the ATP reservoir, and transforming the adenosinergic‐axis‐induced immunosuppressor adenosine into immunopotentiator inosine. Different from the A2A adenosine receptor blockade, this strategy achieves a cascade amplification of ATP‐based anti‐tumor immune response, enabling strong immunogenicity along with reversing the negative feedback of adenosinergic axis for powerfully suppressing tumor progression.
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