Characterization of KRAS Mutational Regression in Oligometastatic Patients
BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-07-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.898561/full |
| _version_ | 1828399693486358528 |
|---|---|
| author | Alessandro Ottaiano Roberta Penta de Vera d’Aragona Anna Maria Trotta Mariachiara Santorsola Maria Napolitano Giosuè Scognamiglio Fabiana Tatangelo Paolo Grieco Silvia Zappavigna Silvia Zappavigna Vincenza Granata Francesco Perri Amalia Luce Amalia Luce Giovanni Savarese Monica Ianniello Marika Casillo Nadia Petrillo Andrea Belli Francesco Izzo Guglielmo Nasti Michele Caraglia Michele Caraglia Stefania Scala |
| author_facet | Alessandro Ottaiano Roberta Penta de Vera d’Aragona Anna Maria Trotta Mariachiara Santorsola Maria Napolitano Giosuè Scognamiglio Fabiana Tatangelo Paolo Grieco Silvia Zappavigna Silvia Zappavigna Vincenza Granata Francesco Perri Amalia Luce Amalia Luce Giovanni Savarese Monica Ianniello Marika Casillo Nadia Petrillo Andrea Belli Francesco Izzo Guglielmo Nasti Michele Caraglia Michele Caraglia Stefania Scala |
| author_sort | Alessandro Ottaiano |
| collection | DOAJ |
| description | BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan–Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02–0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies. |
| first_indexed | 2024-12-10T09:21:07Z |
| format | Article |
| id | doaj.art-5bcd4ae119204d419da8f4d9556a1316 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T09:21:07Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5bcd4ae119204d419da8f4d9556a13162022-12-22T01:54:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.898561898561Characterization of KRAS Mutational Regression in Oligometastatic PatientsAlessandro Ottaiano0Roberta Penta de Vera d’Aragona1Anna Maria Trotta2Mariachiara Santorsola3Maria Napolitano4Giosuè Scognamiglio5Fabiana Tatangelo6Paolo Grieco7Silvia Zappavigna8Silvia Zappavigna9Vincenza Granata10Francesco Perri11Amalia Luce12Amalia Luce13Giovanni Savarese14Monica Ianniello15Marika Casillo16Nadia Petrillo17Andrea Belli18Francesco Izzo19Guglielmo Nasti20Michele Caraglia21Michele Caraglia22Stefania Scala23Istituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyOncohaematology Department, Azienda Ospedaliera di Rilievo Nazionale (A.O.R.N.) Santobono-Pausilipon di Napoli, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Naples, ItalyBiogem Scarl, Institute of Genetic Research, Laboratory of Molecular and Precision Oncology, Ariano Irpino, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Naples, ItalyBiogem Scarl, Institute of Genetic Research, Laboratory of Molecular and Precision Oncology, Ariano Irpino, ItalyAMES, Centro Polidiagnostico Strumentale srl, Naples, ItalyAMES, Centro Polidiagnostico Strumentale srl, Naples, ItalyAMES, Centro Polidiagnostico Strumentale srl, Naples, ItalyAMES, Centro Polidiagnostico Strumentale srl, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Naples, ItalyBiogem Scarl, Institute of Genetic Research, Laboratory of Molecular and Precision Oncology, Ariano Irpino, ItalyIstituto Nazionale Tumori di Napoli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “G. Pascale”, Naples, ItalyBackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan–Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02–0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.898561/fulloligo-metastatic diseasecolorectal cancerKRAScytotoxicityHLA |
| spellingShingle | Alessandro Ottaiano Roberta Penta de Vera d’Aragona Anna Maria Trotta Mariachiara Santorsola Maria Napolitano Giosuè Scognamiglio Fabiana Tatangelo Paolo Grieco Silvia Zappavigna Silvia Zappavigna Vincenza Granata Francesco Perri Amalia Luce Amalia Luce Giovanni Savarese Monica Ianniello Marika Casillo Nadia Petrillo Andrea Belli Francesco Izzo Guglielmo Nasti Michele Caraglia Michele Caraglia Stefania Scala Characterization of KRAS Mutational Regression in Oligometastatic Patients Frontiers in Immunology oligo-metastatic disease colorectal cancer KRAS cytotoxicity HLA |
| title | Characterization of KRAS Mutational Regression in Oligometastatic Patients |
| title_full | Characterization of KRAS Mutational Regression in Oligometastatic Patients |
| title_fullStr | Characterization of KRAS Mutational Regression in Oligometastatic Patients |
| title_full_unstemmed | Characterization of KRAS Mutational Regression in Oligometastatic Patients |
| title_short | Characterization of KRAS Mutational Regression in Oligometastatic Patients |
| title_sort | characterization of kras mutational regression in oligometastatic patients |
| topic | oligo-metastatic disease colorectal cancer KRAS cytotoxicity HLA |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.898561/full |
| work_keys_str_mv | AT alessandroottaiano characterizationofkrasmutationalregressioninoligometastaticpatients AT robertapentadeveradaragona characterizationofkrasmutationalregressioninoligometastaticpatients AT annamariatrotta characterizationofkrasmutationalregressioninoligometastaticpatients AT mariachiarasantorsola characterizationofkrasmutationalregressioninoligometastaticpatients AT marianapolitano characterizationofkrasmutationalregressioninoligometastaticpatients AT giosuescognamiglio characterizationofkrasmutationalregressioninoligometastaticpatients AT fabianatatangelo characterizationofkrasmutationalregressioninoligometastaticpatients AT paologrieco characterizationofkrasmutationalregressioninoligometastaticpatients AT silviazappavigna characterizationofkrasmutationalregressioninoligometastaticpatients AT silviazappavigna characterizationofkrasmutationalregressioninoligometastaticpatients AT vincenzagranata characterizationofkrasmutationalregressioninoligometastaticpatients AT francescoperri characterizationofkrasmutationalregressioninoligometastaticpatients AT amalialuce characterizationofkrasmutationalregressioninoligometastaticpatients AT amalialuce characterizationofkrasmutationalregressioninoligometastaticpatients AT giovannisavarese characterizationofkrasmutationalregressioninoligometastaticpatients AT monicaianniello characterizationofkrasmutationalregressioninoligometastaticpatients AT marikacasillo characterizationofkrasmutationalregressioninoligometastaticpatients AT nadiapetrillo characterizationofkrasmutationalregressioninoligometastaticpatients AT andreabelli characterizationofkrasmutationalregressioninoligometastaticpatients AT francescoizzo characterizationofkrasmutationalregressioninoligometastaticpatients AT guglielmonasti characterizationofkrasmutationalregressioninoligometastaticpatients AT michelecaraglia characterizationofkrasmutationalregressioninoligometastaticpatients AT michelecaraglia characterizationofkrasmutationalregressioninoligometastaticpatients AT stefaniascala characterizationofkrasmutationalregressioninoligometastaticpatients |