"Nature" sub-journal review: "Cancer King" is difficult to deal with, where does immunotherapy get a breakthrough?

!--webeditor: page title" -- Pancreatic ductal adenocarcinoma (PDA) is one of the most deadly cancer types of all solid tumors, which also gives it the title of "King of Cancer".
the current five-year survival rate for primary pancreatic cancer patients is only 7.5 per cent, up only 6.5 per cent from 1 per cent in the 1950s.
lags behind the improvement in survival rates for most other cancer types.
low survival rate in patients with pancreatic cancer is that most patients have no symptoms at an early stage, leading to the disease being at an advanced stage at the time of diagnosis.
another important reason, however, is that pancreatic cancer is highly resistant to most treatments, and even immuno-checkpoint inhibitor therapy, which has revolutionized cancer treatment in recent years, has not performed as well as it would have been satisfactory.
, then, what causes cancer immunotherapy to "do nothing" in the face of pancreatic cancer, and what can be done to break the current impasse.
an in-depth analysis of the problem in a recent review published in the journal Nature.
today, the Pharmaceutical Mingkang content team will share the highlights of this review with readers.
lessons of history and potential hopes that immuno-checkpoint therapy, represented by PD-1/PD-L1 inhibitors, has achieved excellent results in many cancer types.
, however, cancer immunotherapy, which targets checkpoint proteins, has been ineffective in clinical trials for pancreatic cancer (see table below).
even targeting multiple T-cell immune checkpoint proteins at the same time did not significantly improve the patient's response.
, however, clinical trials have also found that levels of neo-antigen in tumors in pancreatic cancer patients are associated with the patient's overall survival, meaning that adaptive immune responses to tumors are a factor in determining the effectiveness of treatment.
, immunosupponsor inhibitors, although ineffective for the entire pancreatic cancer population, showed encouraging results in patients with high microsatellithatic instability (MSI-H).
these studies suggest that it is still possible to stimulate an effective anti-tumor immune response in pancreatic cancer patients, but this requires a rational design of effective countermeasures against immune escape.
, what causes pancreatic cancer to develop resistance to immune checkpoint inhibitors? Pancreatic cancer is unique in that it has multiple mechanisms to evade the anti-tumor immune response of T cells.
addition to altering the cytokines around tumors and setting biochemistry and physical barriers to T-cell migration.
important immunosuppressive factors exist in the tumor microenviron environment of pancreatic cancer, including a variety of myelin cells with immunosuppressive function and microbiomes migrating from the intestines to the pancreas.
Although it has long been thought that a normal pancreas should be a sterile environment, several studies have shown that gut bacteria can invade the pancreas through the liver pancreas, and that the size of bacteria in pancreatic cancer patients can increase by 1,000 times.
the bacteria in these tumors are mainly deformed bacteria (Proteobateria).
Not only are they able to inactivate chemotherapy drugs through an enzyme conversion process, but the resulting metabolites are able to stimulate the proliferation of inhibitory cells (myeloid-derived suppressor cells, MDSCs) from immunosuppressive bone marrow sources by activating Tol-like subjects (TLRs), as well as tumor-associated macrophages (tumor-associated macrophages, TAMs) with anti-inflammatory effects.
addition to the role of the microbiome, pancreatic cancer tumors also release a variety of coercion factors, attracting a large number of myelin cells to the tumor microenviron environment.
, TAMs play a major role in maintaining the immunosuppressive characteristics of tumor micro-environment.
they can promote the differentiation of CD4-positive T cells with immunosuppressive function, thereby weakening the immune response of CD8-positive T-cells.
and in patients with pancreatic cancer, TAMs are able to actively inhibit the growth of CD8-positive cells, thereby suppressing the adaptive immune response.
MDSCs also have the ability to stop cytotoxic CD8-positive T-cell growth.
these multi-pictosant factors, so that the strategy of targeting T-cell immuno-checkpoint protein alone is not sufficient to reverse the immunosuppressive characteristics of tumor micro-environment.
treatment strategies targeting myelin cells and microbiomes because myelin cells are mediated with extensive immunosuppression, how to reverse the invasion and proliferation of myelin cells that promote immune tolerance may be key to the power of checkpoint inhibitors.
currently has several studies exploring treatment strategies that link treatments that target myelin cells with immuno-checkpoint inhibitors.
, CD40 is a highly expressed co-stimulation subject in myelin cells in the tumor microenvironment, activating the immune stimulation characteristics of CD40 that stimulate degenerate cells, and transforming TAMs from esoteric esoterics that aid tumor growth to esoteric esoterics that promote tumor death.
CD40 astrists in combination with chemotherapy or T-cell-targeted therapies has also shown encouraging results in recent clinical trials.
Another target expressed in almost all myelin cells in pancreatic cancer patients is CD11b, which reduces TAM immersion, improves antigen rendering, and has shown remarkable results in combination with checkpoint-based inhibitor-based T-cell therapy.
promising targets include BTK, PI3K gamma, RIP1 kinase, and cytokine and cytokine subjects such as CSF1/CSF1R, CCR2/CXCR2.
, PI3K, and RIP1 signaling pathps that inhibit macrophages can successfully reverse the immunosuppressive characteristics of tumor microenvirons in preclinical models.
in the microbiome that targets pancreatic cancer, the target microbiome with oral antibiotics showed the potential to reverse immunosuppression of myelin cells in experiments.
, however, due to the complexity of the microbiome in the tumor, the targeted microbiome needs a deeper understanding of the biological mechanisms of its role.
, for example, targeting microorganisms that degrade the chemotherapy drug gemcitabine can improve the effectiveness of chemotherapy in colorectal cancer patients.
if pancreatic cancer patients carry the same microorganisms, such targeted therapies could also improve the effectiveness of chemotherapy in pancreatic cancer patients.
, however, a prerequisite for this strategy is that the microbiome in the tumor of pancreatic cancer contains the same bacteria.
!--/ewebeditor:page--!--ewebeditor:page title"--due to the limitations of our understanding of the link between the pancreatic microbiome and disease progression, early research strategies could use strategies used to link oral broad-spectrum antibiotics or phage therapy with cancer immunotherapy to analyze disease responses and/or patient survival, while taking immunologic and microbiome episophageal changes as secondary endpoints.
strategy is immunotherapy in combination with fecal microbial transplantation, which has been shown to be effective in animal models by long-term survivors.
the "good" microbiomes that promote immunotherapy and chemotherapy is an attractive target.
However, due to the complexity of the microbiome and the interdependence of different populations in the microbiome, the treatment strategy for transplanting a single bacterial type may not be easy to succeed, and transplanting multiple bacteria, including "supportive" strains, may be more beneficial to the cultivation of beneficial bacteria.
, a rationally designed combination therapy that produces synergies represents the best hope for improving the prognostication of pancreatic cancer patients.
while the challenges and obstacles to conquering pancreatic cancer are particularly numerous and daunting, the effects of immunosuppressive myelin cells and microbiomes are also present in many other types of cancer.
, integrated treatment strategies to fight pancreatic cancer could become a future treatment model for other types of cancer that are resistant to immunotherapy.
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