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Written | Zhangtailiu renal clear cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, with a rising incidence worldwide
.
ccRCC will undergo spontaneous regression and respond to IL-2 and immune checkpoint inhibitor (CPI) treatment, so it is a tumor type with high immunogenicity, but the degree of tumor mutational burden (TMB) is moderate, and it is "cold" The tumor is comparable
.
In ccRCC, there is no correlation between the responsiveness of TMB and CPI
.
ccRCC is rich in frameshift insertions and deletions (fsINDELs), which are prone to generate new antigens, but the load of fsINDELs cannot be used to predict whether ccRCC patients can benefit from CPI treatment
.
PBRM1 mutations occur in 60% of ccRCCs.
It has been reported that there is a correlation between PBRM1 mutations and CPI responsiveness, but there are different conclusions in different studies
.
Large-scale tumor transcriptome analysis showed that ccRCC is a type of solid tumor with a high degree of immune infiltration, but unlike other tumors, a high degree of immune infiltration is associated with poor post-nephrectomy [1]
.
In CPI treatment, high T/low myeloid cell infiltration and high B cell abundance were enriched in anti-PD-L1 and anti-PD-1 responders, respectively
.
However, cross-validation of these features as predictive biomarkers has produced inconsistent results [2], which may be due to immuno-intratumoral heterogeneity (ITH), especially because previous studies rely on the assessment of individual tumor regions
.
ITH is a common feature of ccRCC and is related to the non-directed diffusion mode and postoperative outcome
.
Therefore, further research is needed to find biomarkers for whether ccRCC responds to CPI and related prognosis
.
Recently, Sergio A.
Quezada from the Cancer Institute of University College London and Samra Turajlic from the Crick Institute published an article Determineants of anti-PD-1 response and resistance in clear cell renal cell carcinoma, ADAPTeR Phase II in Cancer Cell.
The clinical trial recruited 15 patients with metastatic ccRCC to receive nivolumab (anti-PD-1) treatment, and 115 multi-regional tumor samples were taken for comprehensive analysis
.
Genomic analysis showed that the molecular characteristics of tumors are not related to responsiveness, but the expression of ccRCC-specific human endogenous retroviruses is indirectly related to clinical response
.
TCR analysis revealed that responders had a higher number of amplified TCR clones before treatment, indicating the occurrence of an immune response
.
After treatment, responders tend to expand similar TCRs clones that existed before, that is, antigen processing and T cell survival are all directed to the same antigen
.
Among the responders, CD8+ T bound by nivolumab was amplified and expressed GZMK/B
.
Research suggests that nivolumab drives the maintenance and replacement of T cell clones expanded before treatment, but only maintenance is related to treatment response
.
That is to maintain and enhance the existing immune response or the key factor for the effectiveness of anti-PD-1
.
The ADAPTeR Phase II clinical trial recruited 15 patients with metastatic ccRCC to receive nivolumab (anti-PD-1) treatment, and the patients were divided into "responders" and "non-responders" according to different clinical benefits
.
The patient's age, gender, IMDC risk classification, presence of sarcomatoid/rhabdomyoid features, etc.
are not related to response
.
The samples were analyzed by whole exome sequencing, and the molecular characteristics showed typical ccRCC characteristics, with VHL mutations (77%) (the other 15% had VHL methylation), PBRM1 (62%), SETD2 (38%), BAP1 ( 15%), KDM5C (38%) and other mutations
.
But these gene mutations are not related to whether they respond to nivolumab
.
wGII (Chromosome Complexity Index), ITH, somatic cell copy number changes, etc.
have no correlation with responsiveness
.
Previous studies have shown that the presence of cytotoxic T cells in ccRCC tumors and the response to nivolumab are correlated with the expression of human endogenous retrovirus (HERV)
.
The researchers reintegrated and analyzed the expression of HERV, and found that the previously reported HERV sites related to the appearance of cytotoxic T cells and response to CPI were not differentially expressed between responders and non-responders, or were affected by immunotherapy
.
Further analysis found that 10 of the HERV can be used to distinguish between responders and non-responders before or after treatment
.
The transcription of these HERV and LTR elements is highly specific to ccRCC, which reflects the purity of the tumor, and is overexpressed in non-responders before treatment, and is related to the lack of anti-tumor immune response and anti-PD-1 non-response
.
Differential gene expression analysis showed that nivolumab treatment increased T cell infiltration in both responders and non-responders.
Compared with non-responders, responders expressed higher levels of CD3E, CD8A, GZMB and TCF7 after treatment, and Immune activation and TCR signaling pathways are enriched in responders
.
The samples were subjected to immunochemical and multiple immunofluorescence analysis, and it was found that the number of T cells, CD8+/Treg, CD4+/Treg, total PD-1 expression, etc.
were not significantly different between responders and non-responders (before treatment and after treatment)
.
Before treatment, both groups expressed lower GZMB; but after treatment, total GZMB expression and CD8+ T cell-specific GZMB expression increased significantly in responders
.
Subsequently, the researchers analyzed the expansion and replacement of T cell clones during the treatment process and found that the TCR clonality in tumor samples was higher than that in PBMCs, indicating that clonal expansion occurred in the tumor
.
The responders had higher intratumoral TCR clonality before treatment, and there was no significant difference after treatment
.
Track TCR changes, and after treatment, the responders retain more TCR clones that existed before
.
That is, the previously existing amplified TCR clones are more likely to be retained in the tumors of responders and replaced in non-responders
.
Similarly, the clustering of the CDR3 sequence of the amplified TCR clone before and after treatment tends to increase among the responders
.
The researchers further isolated nivolumab-bound CD8+ T cells from tumor samples of responders and non-responders, and performed high-dimensional flow analysis, RNAseq, and single-cell TCR-seq analysis
.
Nivolumab-bound CD8+ T cells up-regulate pro-inflammatory cell/chemokine and T cell activation pathways, regardless of clinical benefit
.
Highly amplified CD8+ clones and higher expression levels of GZMK were observed in the responders
.
Nivolumab-binding CD8+ T cells are related to clonality, that is, Nivolumab binding leads to clonal expansion
.
And among the responders, the amplified clones exist in clusters, most of which are drug-bound, consisting of pre-existing and new TCRs; while the non-responders lack clustered TCRs as a whole
.
Finally, the researchers analyzed the published data and verified that the CD8+ T cells of CPI responders will undergo TCRs expansion and GZMB/K up-regulation
.
In general, the study described the characteristics of the genome and tumor immune microenvironment of metastatic clear cell renal cell carcinoma before and after anti-PD-1 treatment in detail, revealing that patients are responsive to anti-PD-1 The decisive factor may be of reference value for the precision medicine of ccRCC patients
.
Original link: https://doi.
org/10.
1016/j.
ccell.
2021.
10.
001 Platemaker: 11 References 1.
Fridman, WH, Zitvogel, L.
, Saute` s-Fridman, C.
, and Kroemer, G.
(2017).
The immune contexture in cancer prognosis and treatment.
Nat.
Rev.
Clin.
Oncol.
14, 717–734.
2.
Bi, K.
, He, MX, Bakouny, Z.
, Kanodia, A.
, Napolitano, S.
, Wu, J.
, Grimaldi, G.
, Braun, DA, Cuoco, MS, Mayorga, A.
, et al.
(2021).
Tumor and immune re-programming during immunotherapy in advanced renal cell carcinoma.
Cancer Cell 39 , 649–661.
Reprinting instructions [Original Articles] BioArt original articles, personal sharing is welcome, reprinting is prohibited without permission, the copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
ccRCC will undergo spontaneous regression and respond to IL-2 and immune checkpoint inhibitor (CPI) treatment, so it is a tumor type with high immunogenicity, but the degree of tumor mutational burden (TMB) is moderate, and it is "cold" The tumor is comparable
.
In ccRCC, there is no correlation between the responsiveness of TMB and CPI
.
ccRCC is rich in frameshift insertions and deletions (fsINDELs), which are prone to generate new antigens, but the load of fsINDELs cannot be used to predict whether ccRCC patients can benefit from CPI treatment
.
PBRM1 mutations occur in 60% of ccRCCs.
It has been reported that there is a correlation between PBRM1 mutations and CPI responsiveness, but there are different conclusions in different studies
.
Large-scale tumor transcriptome analysis showed that ccRCC is a type of solid tumor with a high degree of immune infiltration, but unlike other tumors, a high degree of immune infiltration is associated with poor post-nephrectomy [1]
.
In CPI treatment, high T/low myeloid cell infiltration and high B cell abundance were enriched in anti-PD-L1 and anti-PD-1 responders, respectively
.
However, cross-validation of these features as predictive biomarkers has produced inconsistent results [2], which may be due to immuno-intratumoral heterogeneity (ITH), especially because previous studies rely on the assessment of individual tumor regions
.
ITH is a common feature of ccRCC and is related to the non-directed diffusion mode and postoperative outcome
.
Therefore, further research is needed to find biomarkers for whether ccRCC responds to CPI and related prognosis
.
Recently, Sergio A.
Quezada from the Cancer Institute of University College London and Samra Turajlic from the Crick Institute published an article Determineants of anti-PD-1 response and resistance in clear cell renal cell carcinoma, ADAPTeR Phase II in Cancer Cell.
The clinical trial recruited 15 patients with metastatic ccRCC to receive nivolumab (anti-PD-1) treatment, and 115 multi-regional tumor samples were taken for comprehensive analysis
.
Genomic analysis showed that the molecular characteristics of tumors are not related to responsiveness, but the expression of ccRCC-specific human endogenous retroviruses is indirectly related to clinical response
.
TCR analysis revealed that responders had a higher number of amplified TCR clones before treatment, indicating the occurrence of an immune response
.
After treatment, responders tend to expand similar TCRs clones that existed before, that is, antigen processing and T cell survival are all directed to the same antigen
.
Among the responders, CD8+ T bound by nivolumab was amplified and expressed GZMK/B
.
Research suggests that nivolumab drives the maintenance and replacement of T cell clones expanded before treatment, but only maintenance is related to treatment response
.
That is to maintain and enhance the existing immune response or the key factor for the effectiveness of anti-PD-1
.
The ADAPTeR Phase II clinical trial recruited 15 patients with metastatic ccRCC to receive nivolumab (anti-PD-1) treatment, and the patients were divided into "responders" and "non-responders" according to different clinical benefits
.
The patient's age, gender, IMDC risk classification, presence of sarcomatoid/rhabdomyoid features, etc.
are not related to response
.
The samples were analyzed by whole exome sequencing, and the molecular characteristics showed typical ccRCC characteristics, with VHL mutations (77%) (the other 15% had VHL methylation), PBRM1 (62%), SETD2 (38%), BAP1 ( 15%), KDM5C (38%) and other mutations
.
But these gene mutations are not related to whether they respond to nivolumab
.
wGII (Chromosome Complexity Index), ITH, somatic cell copy number changes, etc.
have no correlation with responsiveness
.
Previous studies have shown that the presence of cytotoxic T cells in ccRCC tumors and the response to nivolumab are correlated with the expression of human endogenous retrovirus (HERV)
.
The researchers reintegrated and analyzed the expression of HERV, and found that the previously reported HERV sites related to the appearance of cytotoxic T cells and response to CPI were not differentially expressed between responders and non-responders, or were affected by immunotherapy
.
Further analysis found that 10 of the HERV can be used to distinguish between responders and non-responders before or after treatment
.
The transcription of these HERV and LTR elements is highly specific to ccRCC, which reflects the purity of the tumor, and is overexpressed in non-responders before treatment, and is related to the lack of anti-tumor immune response and anti-PD-1 non-response
.
Differential gene expression analysis showed that nivolumab treatment increased T cell infiltration in both responders and non-responders.
Compared with non-responders, responders expressed higher levels of CD3E, CD8A, GZMB and TCF7 after treatment, and Immune activation and TCR signaling pathways are enriched in responders
.
The samples were subjected to immunochemical and multiple immunofluorescence analysis, and it was found that the number of T cells, CD8+/Treg, CD4+/Treg, total PD-1 expression, etc.
were not significantly different between responders and non-responders (before treatment and after treatment)
.
Before treatment, both groups expressed lower GZMB; but after treatment, total GZMB expression and CD8+ T cell-specific GZMB expression increased significantly in responders
.
Subsequently, the researchers analyzed the expansion and replacement of T cell clones during the treatment process and found that the TCR clonality in tumor samples was higher than that in PBMCs, indicating that clonal expansion occurred in the tumor
.
The responders had higher intratumoral TCR clonality before treatment, and there was no significant difference after treatment
.
Track TCR changes, and after treatment, the responders retain more TCR clones that existed before
.
That is, the previously existing amplified TCR clones are more likely to be retained in the tumors of responders and replaced in non-responders
.
Similarly, the clustering of the CDR3 sequence of the amplified TCR clone before and after treatment tends to increase among the responders
.
The researchers further isolated nivolumab-bound CD8+ T cells from tumor samples of responders and non-responders, and performed high-dimensional flow analysis, RNAseq, and single-cell TCR-seq analysis
.
Nivolumab-bound CD8+ T cells up-regulate pro-inflammatory cell/chemokine and T cell activation pathways, regardless of clinical benefit
.
Highly amplified CD8+ clones and higher expression levels of GZMK were observed in the responders
.
Nivolumab-binding CD8+ T cells are related to clonality, that is, Nivolumab binding leads to clonal expansion
.
And among the responders, the amplified clones exist in clusters, most of which are drug-bound, consisting of pre-existing and new TCRs; while the non-responders lack clustered TCRs as a whole
.
Finally, the researchers analyzed the published data and verified that the CD8+ T cells of CPI responders will undergo TCRs expansion and GZMB/K up-regulation
.
In general, the study described the characteristics of the genome and tumor immune microenvironment of metastatic clear cell renal cell carcinoma before and after anti-PD-1 treatment in detail, revealing that patients are responsive to anti-PD-1 The decisive factor may be of reference value for the precision medicine of ccRCC patients
.
Original link: https://doi.
org/10.
1016/j.
ccell.
2021.
10.
001 Platemaker: 11 References 1.
Fridman, WH, Zitvogel, L.
, Saute` s-Fridman, C.
, and Kroemer, G.
(2017).
The immune contexture in cancer prognosis and treatment.
Nat.
Rev.
Clin.
Oncol.
14, 717–734.
2.
Bi, K.
, He, MX, Bakouny, Z.
, Kanodia, A.
, Napolitano, S.
, Wu, J.
, Grimaldi, G.
, Braun, DA, Cuoco, MS, Mayorga, A.
, et al.
(2021).
Tumor and immune re-programming during immunotherapy in advanced renal cell carcinoma.
Cancer Cell 39 , 649–661.
Reprinting instructions [Original Articles] BioArt original articles, personal sharing is welcome, reprinting is prohibited without permission, the copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
